Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas

ABSTRACT

This invention relates to the use of a group of aryl ureas in treating cytokine mediated diseases and proteolytic enzyme mediated diseases, and pharmaceutical compositions for use in such therapy.

FIELD OF THE INVENTION

[0001] This invention relates to the use of a group of aryl ureas intreating cytokine mediated diseases and proteolytic enzyme mediateddiseases, and pharmaceutical compositions for use in such therapy.

BACKGROUND OF THE INVENTION

[0002] Two classes of effector molecules which are critical for theprogression of rheumatoid arthritis are pro-inflammatory cytokines andtissue degrading proteases. Recently, a family of kinases was describedwhich is instrumental in controlling the transcription and translationof the structural genes coding for these effector molecules.

[0003] The mitogen-activated protein (MAP) kinase family is made up of aseries of structurally related proline-directed serine/threonine kinaseswhich are activated either by growth factors (such as EGF) and phorbolesters (ERK), or by IL-1, TNFα or stress (p38, JNK). The MAP kinases areresponsible for the activation of a wide variety of transcriptionfactors and proteins involved in transcriptional control of cytokineproduction. A pair of novel protein kinases involved in the regulationof cytokine synthesis was recently described by a group from SmithKlineBeecham (Lee et al. Nature 1994, 372, 739). These enzymes were isolatedbased on their affinity to bond to a class of compounds, named CSAIDSs(cytokine suppressive anti-inflammatory drugs) by SKB. The CSAIDs,bicyclic pyridinyl imidazoles, have been shown to have cytokineinhibitory activity both in vitro and in vivo. The isolated enzymes,CSBP-1 and -2 (CSAID binding protein 1 and 2) have been cloned andexpressed. A murine homologue for CSBP-2, p38, has also been reported(Han et al. Science 1994, 265, 808).

[0004] Early studies suggested that CSAIDs function by interfering withm-RNA translational events during cytokine biosynthesis. Inhibition ofp38 has been shown to inhibit both cytokine production (eg., TNFα, IL-1,IL-6, IL-8) and proteolytic enzyme production (eg., MMP-1, MMP-3) invitro and/or in vivo.

[0005] Clinical studies have linked TNFα production and/or signaling toa number of diseases including rheumatoid arthritis (Maini. J. RoyalColl. Physicians London 1996, 30, 344). In addition, excessive levels ofTNFα have been implicated in a wide variety of inflammatory and/orimmunomodulatory diseases, including acute rheumatic fever (Yegin et al.Lancet 1997, 349, 170), bone resorption (Pacifici et al. J. Clin.Endocrinol. Metabol. 1997, 82, 29), postmenopausal osteoperosis(Pacifici et al. J. Bone Mineral Res. 1996, 11, 1043), sepsis (Blackwellet al. Br. J. Anaesth. 1996, 77, 110), gram negative sepsis (Debets etal. Prog. Clin. Biol. Res. 1989, 308, 463), septic shock (Tracey et al.Nature 1987, 330, 662; Girardin et al. New England J. Med. 1988, 319,397), endotoxic shock (Beutler et al. Science 1985, 229, 869; Ashkenasiet al. Proc. Nat'l. Acad. Sci. USA 1991, 88, 10535), toxic shocksyndrome, (Saha et al. J. Immunol. 1996, 157, 3869; Lina et al. FEMSImmunol. Med. Microbiol. 1996, 13, 81), systemic inflammatory responsesyndrome (Anon. Crit. Care Med. 1992, 20, 864), inflammatory boweldiseases (Stokkers et al. J. Inflamm. 1995-6, 47, 97) including Crohn'sdisease (van Deventer et al. Aliment. Pharmacol. Therapeu. 1996, 10(Suppl. 2), 107; van Dullemen et al. Gastroenterology 1995, 109, 129)and ulcerative colitis (Masuda et al. J. Clin. Lab. Immunol. 1995, 46,111), Jarisch-Herxheimer reactions (Fekade et al. New England J. Med.1996, 335, 311), asthma (Amrani et al. Rev. Malad. Respir. 1996, 13,539), adult respiratory distress syndrome (Roten et al. Am. Rev. Respir.Dis. 1991, 143, 590; Suter et al. Am. Rev. Respir. Dis. 1992, 145,1016), acute pulmonary fibrotic diseases (Pan et al. Pathol. Int. 1996,46, 91), pulmonary sarcoidosis (Ishioka et al. Sarcoidosis VasculitisDiffuse Lung Dis. 1996, 13, 139), allergic respiratory diseases (Casaleet al. Am. J. Respir. Cell Mol. Biol. 1996, 15, 35), silicosis (Gossartet al. J. Immunol. 1996, 156, 1540; Vanhee et al. Eur. Respir. J. 1995,8, 834), coal worker's pneumoconiosis (Borm et al. Am. Rev. Respir. Dis.1988, 138, 1589), alveolar injury (Horinouchi et al. Am. J. Respir. CellMol. Biol. 1996, 14, 1044), hepatic failure (Gantner et al. J.Pharmacol. Exp. Therap. 1997, 280, 53), liver disease during acuteinflammation (Kim et al. J. Biol. Chem. 1997, 272, 1402), severealcoholic hepatitis (Bird et al. Ann. Intern. Med. 1990, 112, 917),malaria (Grau et al. Immunol. Rev. 1989, 112, 49; Taverne et al.Parasitol. Today 1996, 12, 290) including Plasmodium falciparum malaria(Perlmann et al. Infect. Immunit. 1997, 65, 116) and cerebral malaria(Rudin et al. Am. J. Pathol. 1997, 150, 257), non-insulin-dependentdiabetes mellitus (NIDDM; Stephens et al. J. Biol. Chem. 1997, 272, 971;Ofei et al. Diabetes 1996, 45, 881), congestive heart failure (Doyama etal. Int. J. Cardiol. 1996, 54, 217; McMurray et al. Br. Heart J. 1991,66, 356), damage following heart disease (Malkiel et al. Mol. Med. Today1996, 2, 336), atherosclerosis (Parums et al. J. Pathol 1996, 179, A46),Alzheimer's disease (Fagarasan et al. Brain Res. 1996, 723, 231; Aisenet al. Gerontology 1997, 43, 143), acute encephalitis (Ichiyama et al.J. Neurol. 1996, 243, 457), brain injury (Cannon et al. Crit. Care Med.1992, 20, 1414; Hansbrough et al. Surg. Clin. N. Am. 1987, 67, 69;Marano et al. Surg. Gynecol. Obstetr. 1990, 170, 32), multiple sclerosis(M.S.; Coyle. Adv. Neuroimmunol. 1996, 6, 143; Matusevicius et al. J.Neuroimmunol. 1996, 66, 115) including demyelation and oligiodendrocyteloss in multiple sclerosis (Brosnan et al. Brain Pathol. 1996, 6, 243),advanced cancer (MucWierzgon et al. J. Biol. Regulators HomeostaticAgents 1996, 10, 25), lymphoid malignancies (Levy et al. Crit. Rev.Immunol. 1996, 16, 31), pancreatitis (Exley et al. Gut 1992, 33, 1126)including systemic complications in acute pancreatitis (McKay et al. Br.J. Surg. 1996, 83, 919), impaired wound healing in infectioninflammation and cancer (Buck et al. Am. J. Pathol. 1996, 149, 195),myelodysplastic syndromes (Raza et al. Int. J. Hematol. 1996, 63, 265),systemic lupus erythematosus (Maury et al. Arthritis Rheum. 1989, 32,146), biliary cirrhosis (Miller et al. Am. J. Gasteroenterolog. 1992,87, 465), bowel necrosis (Sun et al. J. Clin. Invest. 1988, 81, 1328),psoriasis (Christophers. Austr. J. Dermatol. 1996, 37, S4), radiationinjury (Redlich et al. J. Immunol. 1996, 157, 1705), and toxicityfollowing administration of monoclonal antibodies such as OKT3 (Brod etal. Neurology 1996, 46, 1633). TNFα levels have also been related tohost-versus-graft reactions (Piguet et al. Immunol. Ser. 1992, 56, 409)including ischemia reperfusion injury (Colletti et al. J. Clin. Invest.1989, 85, 1333) and allograft rejections including those of the kidney(Maury et al. J. Exp. Med. 1987, 166, 1132), liver (Inagawa et al.Transplantation 1990, 50, 219), heart (Bolling et al. Transplantation1992, 53, 283), and skin (Stevens et al. Transplant. Proc. 1990, 22,1924), lung allograft rejection (Grossman et al. Immunol. Allergy Clin.N. Am. 1989, 9, 153) including chronic lung allograft rejection(obliterative bronchitis; LoCicero et al. J. Thorac. Cardiovasc. Surg.1990, 99, 1059), as well as complications due to total hip replacement(Cirino et al. Life Sci. 1996, 59, 86). TNFα has also been linked toinfectious diseases (review: Beutler et al. Crit. Care Med. 1993, 21,5423; Degre. Biotherapy 1996, 8, 219) including tuberculosis (Rook etal. Med. Malad. Infect. 1996, 26, 904), Helicobacter pylori infectionduring peptic ulcer disease (Beales et al. Gastroenterology 1997, 112,136), Chaga's disease resulting from Trypanosoma cruzi infection(Chandrasekar et al. Biochem. Biophys. Res. Commun. 1996, 223, 365),effects of Shiga-like toxin resulting from E. coli infection (Harel etal. J. Clin. Invest. 1992, 56, 40), the effects of enterotoxin Aresulting from Staphylococcus infection (Fischer et al. J. Immunol.1990, 144, 4663), meningococcal infection (Waage et al. Lancet 1987,355; Ossege et al. J. Neurolog. Sci. 1996, 144, 1), and infections fromBorrelia burgdorferi (Brandt et al. Infect. Immunol. 1990, 58, 983),Treponema pallidum (Chamberlin et al. Infect. Immunol. 1989, 57, 2872),cytomegalovirus (CMV; Geist et al. Am. J. Respir. Cell Mol. Biol 1997,16, 31), influenza virus (Beutler et al. Clin. Res. 1986, 34, 491 a),Sendai virus (Goldfield et al. Proc. Nat'l. Acad. Sci. USA 1989, 87,1490), Theiler's encephalomyelitis virus (Sierra et al. Immunology 1993,78, 399), and the human immunodeficiency virus (HIV; Poli. Proc. Nat'l.Acad. Sci. USA 1990, 87, 782; Vyakaram et al. AIDS 1990, 4, 21; Badleyet al. J. Exp. Med. 1997, 185, 55).

[0006] Because inhibition of p38 leads to inhibition of TNFα production,p38 inhibitors will be useful in treatment of the above listed diseases.

[0007] A number of diseases are thought to be mediated by excess orundesired matrixdestroying metalloprotease (MMP) activity or by animbalance in the ratio of the MMPs to the tissue inhibitors ofmetalloproteinases (TIMPs). These include osteoarthritis (Woessner etal. J. Biol. Chem. 1984, 259, 3633), rheumatoid arthritis (Mullins etal. Biochim. Biophys. Acta 1983, 695, 117; Woolley et al. ArthritisRheum. 1977, 20, 1231; Gravallese et al. Arthritis Rheum. 1991, 34,1076), septic arthritis (Williams et al. Arthritis Rheum. 1990, 33,533), tumor metastasis (Reich et al. Cancer Res. 1988, 48, 3307;Matrisian et al. Proc. Nat'l. Acad. Sci., USA 1986, 83, 9413),periodontal diseases (Overall et al. J. Periodontal Res. 1987, 22, 81),corneal ulceration (Bums et al. Invest. Opthalmol. Vis. Sci. 1989, 30,1569), proteinuria (Baricos et al. Biochem. J. 1988, 254, 609), coronarythrombosis from atherosclerotic plaque rupture (Henney et al. Proc.Nat'l. Acad. Sci., USA 1991, 88, 8154), aneurysmal aortic disease (Vineet al. Clin. Sci. 1991, 81, 233), birth control (Woessner et al.Steroids 1989, 54, 491), dystrophobic epidermolysis bullosa (Kronbergeret al. J. Invest. Dermatol. 1982, 79, 208), degenerative cartilage lossfollowing traumatic joint injury, osteopenias mediated by MMP activity,tempero mandibular joint disease, and demyelating diseases of thenervous system (Chantry et al. J. Neurochem. 1988, 50, 688).

[0008] Because inhibition of p38 leads to inhibition of MMP production,p38 inhibitors will be useful in treatment of the above listed diseases.

[0009] Inhibitors of p38 are active in animal models of TNFα production,including a muirne lipopolysaccharide (LPS) model of TNFα production.Inhibitors of p38 are active in a number of standard animal models ofinflammatory diseases, including carrageenan-induced edema in the ratpaw, arachadonic acid-induced edema in the rat paw, arachadonicacid-induced peritonitis in the mouse, fetal rat long bone resorption,murine type II collagen-induced arthritis, and Fruend's adjuvant-inducedarthritis in the rat. Thus, inhibitors of p38 will be useful in treatingdiseases mediated by one or more of the above-mentioned cytokines and/orproteolytic enzymes.

[0010] The need for new therapies is especially important in the case ofarthritic diseases. The primary disabling effect of osteoarthritis,rheumatoid arthritis and septic arthritis is the progressive loss ofarticular cartilage and thereby normal joint function. No marketedpharmaceutical agent is able to prevent or slow this cartilage loss,although nonsteroidal antiinflammatory drugs (NSAIDs) have been given tocontrol pain and swelling. The end result of these diseases is totalloss of joint function which is only treatable by joint replacementsurgery. P38 inhibitors will halt or reverse the progression ofcartilage loss and obviate or delay surgical intervention.

[0011] Several patents have appeared claiming polyarylimidazoles and/orcompounds containing polyarylimidazoles as inhibitors of p38 (forexample, Lee et al. WO 95/07922; Adams et al. WO 95/02591; Adams et al.WO 95/13067; Adams et al. WO 95/31451). It has been reported thatarylimidazoles complex to the ferric form of cytochrome P450_(cam)(Harris et al. Mol. Eng. 1995, 5, 143, and references therein), causingconcern that these compounds may display structure-related toxicity(Howard-Martin et al. Toxicol. Pathol. 1987, 15, 369). Therefore, thereremains a need for improved p38 inhibitors.

SUMMARY OF THE INVENTION

[0012] This invention provides compounds, generally described as arylureas, including both aryl and heteroaryl analogues, which inhibit p38mediated events and thus inhibit the production of cytokines (such asTNFα, IL-1 and IL-8) and proteolytic enzymes (such as MMP-1 and MMP-3).The invention also provides a method of treating a cytokine mediateddisease state in humans or mammals, wherein the cytokine is one whoseproduction is affected by p38. Examples of such cytokines include, butare not limited to TNFα, IL-1 and IL-8. The invention also provides amethod of treating a protease mediated disease state in humans ormammals, wherein the protease is one whose production is affected byp38. Examples of such proteases include, but are not limited tocollagenase (MMP-1) and stromelysin (MMP-3).

[0013] Accordingly, these compounds are useful therapeutic agents forsuch acute and chronic inflammatory and/or immunomodulatory diseases asrheumatoid arthritis, osteoarthritis, septic arthritis, rheumatic fever,bone resorption, postmenopausal osteoperosis, sepsis, gram negativesepsis, septic shock, endotoxic shock, toxic shock syndrome, systemicinflammatory response syndrome, inflammatory bowel diseases includingCrohn's disease and ulcerative colitis, Jarisch-Herxheimer reactions,asthma, adult respiratory distress syndrome, acute pulmonary fibroticdiseases, pulmonary sarcoidosis, allergic respiratory diseases,silicosis, coal worker's pneumoconiosis, alveolar injury, hepaticfailure, liver disease during acute inflammation, severe alcoholichepatitis, malaria including Plasmodium falciparum malaria and cerebralmalaria, non-insulin-dependent diabetes mellitus (NIDDM), congestiveheart failure, damage following heart disease, atherosclerosis,Alzheimer's disease, acute encephalitis, brain injury, multiplesclerosis including demyelation and oligiodendrocyte loss in multiplesclerosis, advanced cancer, lymphoid malignancies, tumor metastasis,pancreatitis, including systemic complications in acute pancreatitis,impaired wound healing in infection, inflammation and cancer,periodontal diseases, corneal ulceration, proteinuria, myelodysplasticsyndromes, systemic lupus erythematosus, biliary cirrhosis, bowelnecrosis, psoriasis, radiation injury, toxicity following administrationof monoclonal antibodies such as OKT3, host-versus-graft reactionsincluding ischemia reperfusion injury and allograft rejections includingkidney, liver, heart, and skin allograft rejections, lung allograftrejection including chronic lung allograft rejection (obliterativebronchitis) as well as complications due to total hip replacement, andinfectious diseases including tuberculosis, Helicobacter pyloriinfection during peptic ulcer disease, Chaga's disease J resulting fromTrypanosoma cruzi infection, effects of Shiga-like toxin resulting fromE. coli infection, effects of enterotoxin A resulting fromStaphylococcus infection, meningococcal infection, and infections fromBorrelia burgdorferi, Treponema pallidum, cytomegalovirus, influenzavirus, Theiler's encephalomyelitis virus, and the human immunodeficiencyvirus (HIV).

[0014] The present invention, therefore, provides compounds generallydescribed as aryl ureas, including both aryl and heteroaryl analogues,which inhibit the p38 pathway. The invention also provides a method fortreatment of p38-mediated disease states in humans or mammals, e.g.,disease states mediated by one or more cytokines or proteolytic enzymesproduced and/or activated by a p38 mediated process. Thus, the inventionis directed to compounds and methods for the treatment of diseasesmediated by p38 kinase comprising administering a compound of Formula I

[0015] wherein

[0016] B is a substituted or unsubstituted, up to tricyclic aryl orheteroaryl moiety of up to 30 carbon atoms with at least one 6-memberaromatic structure containing 0-4 members of the group consisting ofnitrogen, oxygen and sulfur, wherein if B is substituted, it issubstituted by one or more substituents selected from the groupconsisting of halogen, up to per-halo, and W_(n), wherein n is 0-3 andeach W is independently selected from the group consisting of —CN,—CO₂R⁷, —C(O)NR⁷R⁷, —C(O)—R⁷, —NO₂, —OR⁷, —SR⁷, —NR⁷R⁷, —NR⁷C(O)OR⁷,—NR⁷C(O)R⁷, C₁-C₁₀ alkyl, C₂₋₁₀-alkenyl, C₁₋₁₀-alkoxy, C₃-C₁₀cycloaklyl, C₆-C₁₄ aryl, C₇-C₂₄ alkaryl, C₃-C₁₃ heteroaryl, C₄-C₂₃alkheteroaryl, substituted C₁-C₁₀ alkyl, substituted C₂₋₁₀-alkenyl,substituted C₁₋₁₀-alkoxy, substituted C₃-C₁₀ cycloalkyl, substitutedC₄-C₂₃ alkheteroaryl and Q—Ar;

[0017] wherein if W is a substituted group, it is substituted by one ormore substituents independently selected from the group consisting of—CN, —CO₂R⁷, —C(O)R⁷, —C(O)NR⁷R⁷, —OR⁷, —SR⁷, —NR⁷R⁷, NO₂, —NR⁷C(O)R⁷,—NR⁷C(O)OR⁷ and halogen up to per-halo;

[0018] wherein each R⁷ is independently selected from H, C₁-C₁₀ alkyl,C₂₋₁₀-alkenyl, C₃-C₁₀ cycloalkyl, C₆-C₁₄ aryl, C₃-C₁₃ hetaryl, C₇-C₂₄alkaryl, C₄-C₂₃ alkheteroaryl, up to per-halosubstituted C₁-C₁₀ alkyl,up to per-halosubstituted C₂₋₁₀-alkenyl, up to per-halosubstitutedC₃-C₁₀ cycloalkyl, up to per-halosubstituted C₆-C₁₄ aryl and up toper-halosubstituted C₃-C₁₃ hetaryl,

[0019] wherein Q is —O—, —S—, —N(R⁷)—, —(CH₂)—_(m), —C(O)—, —CH(OH)—,—(CH₂)_(m)O—, —NR⁷C(O)NR⁷R^(7′)—, —NR⁷C(O)—, —C(O)NR⁷—, —(CH₂)_(m)S—,—(CH₂)_(m)N(R⁷)—, —O(CH₂)_(m)—, —CHX^(a), —CX^(a) ₂—, —S—(CH₂)_(m)— and—N(R⁷)(CH₂)_(m)—,

[0020] m=1-3, and X^(a) is halogen; and Ar is a 5-10 member aromaticstructure containing 0-2 members of the group consisting of nitrogen,oxygen and sulfur, which is unsubstituted or substituted by halogen upto per-halo and optionally substituted by Z_(n1), wherein _(n1) is 0 to3 and each Z is independently selected from the group consisting of of—CN, —CO₂R⁷, —C(O)NR⁷R⁷, —C(O)—NR⁷, —C(O)R⁷, —NO₂, —OR⁷, —SR⁷, —NR⁷R⁷,—NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₆-C₁₄ aryl,C₃-C₁₃ hetaryl, C₇-C₂₄ alkaryl, C₄-C₂₃ alkheteroaryl, substituted C₁-C₁₀alkyl, substituted C₃-C₁₀ cycloalkyl, substituted C₇-C₂₄ alkaryl andsubstituted C₄-C₂₃ alkheteroaryl; wherein the one or more substituentsof Z is selected from the group consisting of —CN, —CO₂R⁷, —C(O)NR⁷R⁷,—OR⁷, —SR⁷, —NO₂, —NR⁷R⁷, —NR⁷C(O)R⁷, —NR⁷C(O)OR⁷,

[0021] R^(3′), R^(4′), R^(5′) are each independently H, C₁₋₁₀-alkyl,optionally substituted by halogen, up to perhalo, C₁₋₁₀ alkoxy,optionally substituted by halogen, up to perhaloalkoxy, halogen; NO₂ orNH₂;

[0022] R^(6′) is H, C₁₋₁₀-alkyl, C₁₋₁₀ alkoxy, —NHCOR¹; —NR¹COR¹; NO₂;

[0023] one of R^(4′), R^(5′) or R^(6′) can be —X—Y,

[0024] or 2 adjacent R^(4′)—R^(6′) can together be an aryl or hetarylring with 5-12 atoms, optionally substituted by C₁₋₁₀-alkyl, C₁₋₁₀alkoxy, C₃₋₁₀ cycloalkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ alkanoyl, C₆₋₁₂ aryl,C₅₋₁₂ hetaryl or C₆₋₁₂ aralkyl;

[0025] R¹ is C₁₋₁₀-alkyl optionally substituted by halogen, up toperhalo;

[0026] X is —CH₂—, —S—, —N(CH₃)—, —NHC(O)—, —CH₂—S—, —S—CH₂—, —C(O)—, or—O—; and

[0027] X is additionally a single bond where Y is pyridyl;

[0028] Y is phenyl, pyridyl, naphthyl, pyridone, pyrazine, benzodioxane,benzopyridine, pyrimidine or benzothiazole, each optionally substitutedby

[0029] C₁₋₁₀-alkyl, C₁₋₁₀-alkoxy, halogen, OH, —SCH₃ or NO₂ or, where Yis phenyl, by

[0030] or a pharmaceutically acceptable salt thereof.

[0031] Preferably, the compounds of formula I are of formula Ia

[0032] wherein

[0033] R³, R⁴, R⁵ and R⁶ are each independently H, halogen, C₁₋₁₀-alkyloptionally substituted by halogen, up to perhalo, C₁₋₁₀-alkoxy,optionally substituted by at least one hydroxy group or by halogen, upto perhalo; C₆₋₁₂ aryl, optionally substituted by C₁₋₁₀ alkoxy orhalogen, C₅₋₁₂ hetaryl, optionally substitued by C₁₋₁₀ alkyl, C₁₋₁₀alkoxy or halogen; NO₂, SO₂F or —SO₂CH_(p)X_(3-p); —COOR¹; —OR¹CONHR¹;—NHCOR¹; —SR¹; phenyl optionally substituted by halo or C₁₋₁₀-alkoxy;NH₂; —N(SO₂R¹)₂, furyloxy,

[0034] 2 adjacent R³-R⁶ can together form an aryl or hetaryl ring with5-12 atoms, optionally substituted by C₁₋₁₀-alkyl, C₁₋₁₀-alkoxy,C₃₋₁₀-cycloalkyl, C₂₋₁₀-alkenyl, C₁₋₁₀-alkanoyl, C₆₋₁₂-aryl,C₅₋₁₂-hetaryl, C₆₋₁₂-aralkyl, C₆₋₁₂-alkaryl, halogen; —NR¹; —NO₂; —CF₃;—COOR¹; —NHCOR¹; —CN; —CONR¹R¹; —SO₂R²; —SOR²; —SR²; in which R¹ is H orC₁₋₁₀-alkyl and R² is C₁₋₁₀-alkyl; optionally substituted by halogen, upto perhalo, with —SO₂-optionally incorporated in the aryl or hetarylring;

[0035] one of R⁴, R⁵ or R⁶ can be —X—Y,

[0036] R¹ is C₁₋₁₀-alkyl, optionally substituted by halogen, up toperhalo;

[0037] p is 0 or 1;

[0038] X is —CH₂, —S—, N(CH₃)—, —NHC(O), CH₂—S—, —S—CH₂—, —C(O)—, or—O—; and

[0039] Y is phenyl, pyridyl, naphthyl, pyridone, pyrazine, benzodixane,benzopyridine, pyrimidine or benzothiazole, each optionally substitutedby C₁₋₁₀-alkyl, C₁₋₁₀-alkoxy, halogen or NO₂ or, where Y is phenyl, by

[0040] with the proviso that if R³ and R⁶ are both H, one of R⁴ or R⁵ isnot H.

[0041] In formula I, suitable hetaryl groups B include, but are notlimited to, 5-12 carbon-atom aromatic rings or ring systems containing1-3 rings, at least one of which is aromatic, in which one or more,e.g., 1-4 carbon atoms in one or more of the rings can be replaced byoxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. Forexample, B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-,2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl,2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-,4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4-or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,3,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3-or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6-or 7-benzoturyl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-,5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5- 6- or7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benz-1,3-oxadiazolyl, 2-, 3-,4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl,1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or9-acridinyll, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionallyoptionally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl,3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. For example, Bcan be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl,1-methyl-3-pyrryl, 1-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or5-methyl-1,2,4-thiadiazol-2-yl.

[0042] Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy,etc. throughout include methyl, ethyl, propyl, butyl, etc., includingall straight-chain and branched isomers such as isopropyl, isobutyl,sec-butyl, tert-butyl, etc.

[0043] Suitable aryl groups include, for example, phenyl and 1- and2-naphthyl.

[0044] The term “cycloalkyl”, as used herein, refers to cyclicstructures with or without alkyl substitutents such that, for example,“C₄ cycloakyl” includes methyl substituted cyclopropyl groups as well ascyclobutyl groups. The term “cycloalkyl” also includes saturatedheterocyclic groups.

[0045] Suitable halogen groups include F, Cl, Br, and/or I, from one toper-substitution (i.e. all H atoms on a group replaced by a halogenatom) being possible where an alkyl group is substituted by halogen,mixed substitution of halogen atom types also being possible on a givenmoiety.

[0046] Preferred compounds of formula I include those where R³ is H,halogen or C₁₋₁₀-alkyl, optionally substituted by halogen, up toperhalo, NO₂, —SO₂F, —SO₂CHF₂; or —SO₂CF₃; R⁴ is H, C₁₋₁₀-alkyl,C₁₋₁₀-alkoxy, halogen or NO₂; R⁵ is H, C₁₋₁₀-alkyl optionallysubstituted by halogen, up to perhalo; R⁶ is H, hydroxy, C₁₋₁₀-alkoxy,optionally substituted by at least one hydroxy group; —COOR¹;—OR¹CONHR¹; —NHCOR¹; —SR¹; phenyl optionally substituted by halo orC₁₋₁₀-alkoxy; NH₂; —N(SO₂R¹)₂, furyloxy,

[0047] Preferably, R³ is Cl, F, C₄₋₅-branched alkyl, —SO₂F or —SO₂CF₃;and R⁶ is hydroxy; C₁₋₁₀-alkoxy optionally substituted by at least onehydroxy group; —COOR¹; —OR¹CONHR¹; —NHCOR¹; —SR¹; phenyl optionallysubstituted by halo or C₁₋₁₀-alkoxy; NH₂; —N(SO₂R¹)₂, furyloxy,

[0048] More preferably, R⁶ is t-butyl or CF₃ and R⁶ is —OCH₃.Preferably, R^(4′) is C₁₋₁₀-alkyl or halogen; R^(5′) is H, C₁₋₁₀-alkyl,halogen, CF₃, halogen, NO₂ or NH₂; and R^(6′) is H, C₁₋₁₀-alkyl,halogen, —NHCOCH₃, —N(CH₃)COCH₃, NO₂,

[0049] The invention also relates to compounds per se, of formula II

[0050] wherein

[0051] R³, R⁴, R⁵ and R⁶ are each independently H, halogen, C₁₋₁₀-alkyloptionally substituted by halogen up to perhalo, C₁₋₁₀-alkoxy,optionally substituted by at least one hydroxy group or halogen, up toperhalo; NO₂, SO₂F or —SO₂CH_(n)X_(3-n), C₁₋₁₀-alkoxy; —COOR¹;—OR¹CONHR¹; —NHCOR¹; —SR¹; C₆₋₁₂ aryl, optionally substituted byC₁₋₁₀-alkyl, C₁₋₁₀ alkoxy or halogen, C₅₋₁₂ hetaryl, optionallysubstituted by C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy or halogen; NH₂; —N(SO₂R¹)₂;furyloxy;

[0052] 2 adjacent R³-R⁶ can together form an aryl or hetaryl ring with5-12 atoms, optionally substituted by C₁₋₁₀-alkyl, C₁₋₁₀-alkoxy,C₃₋₁₀-cycloalkyl, C₂₋₁₀-alkenyl, C₁₋₁₀-alkanoyl, C₆₋₁₂-aryl,C₅₋₁₂-hetaryl, C₆₋₁₂-aralkyl, C₆₋₁₂-alkaryl, halogen; —NR¹; —NO₂; —CF₃;—COOR¹; —NHCOR¹; —CN; —CONR¹R¹; —SO₂R²; —SOR²; —SR²; in which R¹ is H orC₁₋₁₀-alkyl and R² is C₁₋₁₀-alkyl;

[0053] R^(3′), R^(4′) and R^(5′) are each independently H, C₁₋₁₀-alkyl,optionally substituted by halogen, up to perhalo; NO₂ or NH₂;

[0054] R^(6′) is H, C₁₋₁₀-alkyl, halogen, —NHCOR¹; —NR¹COR¹; NO₂;

[0055] 2 adjacent R^(4′)-R^(6′) can together be an aryl or hetaryl ringwith 5-12 atoms;

[0056] R¹ is C₁₋₁₀-alkyl, optionally substituted by halogen, up toperhalo;

[0057] n is 0 or 1;

[0058] with the provisos that

[0059] (a) if R³ and R⁶ are both H , one of R⁴ or R⁵ is not H, and

[0060] (b) that R⁶ is phenyl substituted by alkoxy or halogen, alkoxysubstituted by hydroxy, —SO₂CF₂H, —OR¹CONHR¹,

[0061] furyloxy or —N(SO₂R¹)₂; or R^(6′) is

[0062] and (c) if R⁶ is phenyl substituted by alkoxy or halogen, thecompounds have a pKa greater than 10, e.g., greater than 12, preferablygreater than 15.

Preferred 5-tert-butylphenyl Ureas Are

[0063] N-(5-tert-Butyl-2-methoxyphenyl)-N′-(4-phenyloxphenyl)urea;

[0064]N-(5-tert-Butyl-2-methoxyphenyl)-N′-(4-(4-methoxyphenyloxy)phenyl)urea;

[0065]N-(5-tert-Butyl-2-methoxyphenyl)-N′-(4-(4-pyridinyloxy)phenyl)urea;

[0066]N-(5-tert-Butyl-2-methoxyphenyl)-N′-(4-(4-pyridinylmethyl)phenyl)urea;

[0067]N-(5-tert-Butyl-2-methoxyphenyl)-N′-(4-(4-pyridinylthio)phenyl)urea;

[0068]N-(5-tert-Butyl-2-methoxyphenyl)-N′-(4-(4-(4,7-methano-1H-isoindole-1,3(2H)-dionyl)methyl)phenyl)uera;

[0069] N-(5-tert-Butyl-2-phenylphenyl)-N′-(2,3-dichlorophenyl)urea;

[0070] N-(5-tert-Butyl-2-(3-thienyl)phenyl)-N′-(2,3-dichlorophenyl)urea;

[0071]N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N′-(2,3-dichlorophenyl)urea;

[0072]N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N′-(1-naphthyl)urea;

[0073]N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N′-(2,3-dichlorophenyl)urea;

[0074]N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N′-(1-naphthyl)urea;

[0075]N-(5-tert-Butyl-2-(3-tetrahydrofuranyloxy)phenyl)-N′-(2,3-dichlorophenyl)urea;and

[0076]N-(5-tert-Butyl-2-methoxyphenyl)-N′-(4-(3-pyridinyl)methylphenyl)urea.

Preferred 5-trifuoromethylphenyl Ureas Are

[0077] N-(5-Trifluoromethyl-2-methoxyphenyl)-N′-(4-methylphenyl)urea;

[0078]N-(5-Trifluoromethyl-2-methoxyphenyl)-N′-(4-methyl-2-fluorophenyl)urea;

[0079]N-(5-Trifluoromethyl-2-methoxyphenyl)-N′-(4-fluoro-3-chlorophenyl)urea;

[0080]N-(5-Trifluoromethyl-2-methoxyphenyl)-N′-(4-methyl-3-chlorophenyl)urea;

[0081]N-(5-Trifluoromethyl-2-methoxyphenyl)-N′-(4-methyl-3-fluorophenyl)urea;

[0082]N-(5-Trifluoromethyl-2-methoxyphenyl)-N′-(2,4-difluorophenyl)urea;

[0083]N-(5-Trifluoromethyl-2-methoxyphenyl)-N′-(4-phenyloxy-3,5-dichlorophenyl)urea;

[0084]N-(5-Trifluoromethyl-2-methoxyphenyl)-N′-(4-(4-pyridinylmethyl)phenyl)urea;

[0085]N-(5-Trifluoromethyl-2-methoxyphenyl)-N′-(4-(4-pyridinylthio)phenyl)urea;

[0086]N-(5-Trifluoromethyl-2-methoxyphenyl)-N′-(4-(4-pyridinyloxy)phenyl)urea;

[0087]N-(5-Trifluoromethyl-2-methoxyphenyl)-N′-(3-(4-pyridinylthio)phenyl)urea;and

[0088]N-(5-Trifluoromethyl-2-methoxyphenyl)-N′-(4-(3-(N-methylaminocarbonyl)-phenyloxy)phenyl)-urea.

Preferred 5-sulfonylphenyl Ureas Are

[0089] N-(5-Fluorosulfonyl)-2-methoxyphenyl)-N′-(4-methylphenyl)urea;

[0090]N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N′-(4-methylphenyl)ureaN-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N′-(4-fluorophenyl)uera;

[0091]N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N′-(4-methyl-2-fluorophenyl)urea;

[0092]N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N′-(4-methyl-3-fluorophenyl)urea;

[0093]N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N′-(4-methyl-3-chlorophenyl)urea;

[0094]N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N′-(4-fluoro-3-chlorophenyl)urea;

[0095]N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N′-(4-fluoro-3-methylphenyl)uera;

[0096]N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N′-(2,3-dimethylphenyl)urea;and

[0097]N-(5-(Trifluoromethanesulfonyl)-2-methoxphenyl)-N′-(4-methylphenyl)urea.

Preferred 2-naphthyl Ureas Are

[0098] N-(3-Methoxy-2-naphthyl)-N′-(2-fluorophenyl)urea;

[0099] N-(3-Methoxy-2-naphthyl)-N′-(4-methylphenyl)urea;

[0100] N-(3-Methoxy-2-naphthyl)-N′-(3-fluorophenyl)urea;

[0101] N-(3-Methoxy-2-naphthyl)-N′(4-methyl-3-fluorophenyl)urea;

[0102] N-(3-Methoxy-2-naphthyl)-N′-(2,3-dimethylphenyl)urea;

[0103] N-(3-Methoxy-2-naphthyl)-N′-(1-naphthyl)urea;

[0104] N-(3-Methoxy-2-naphthyl)-N′-(4-(4-pyridinylmethyl)phenyl)urea;

[0105] N-(3-Methoxy-2-naphthyl)-N′-(4-(4-pyridinylthio)phenyl)urea;

[0106] N-(3-Methoxy-2-naphthyl)-N′-(4-(4-methoxyphenyloxy)phenyl)urea;and

[0107]N-(3-Methoxy-2-naphthyl)-N′-(4-(4-(4,7-methano-1H-isoindole-1,3(2H)-dionyl)methyl)phenyl)uera.

Other Preferred Ureas Are

[0108] N-(2-Hydroxy-4-nitro-5-chlorophenyl)-N′-(phenyl)urea; and

[0109]N-(2-Hydroxy-4-nitro-5-chlorophenyl)-N′-(4-(4-pyridinylmethly)phenyl)urea.

[0110] The present invention is also directed to pharmaceuticallyacceptable salts of formula I. Suitable pharmaceutically acceptablesalts are well known to those skilled in the art and include basic saltsof inorganic and organic acids, such as hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, methanesulphonic acid, sulphonicacid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid,citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid,maleic acid, benzoic acid, salicylic acid, phenylacetic acid, andmandelic acid. In addition, pharmaceutically acceptable salts includeacid salts of inorganic bases, such as salts containing alkaline cations(e.g., Li⁺ Na⁺ or K⁺), alkaline earth cations (e.g., Mg⁺², Ca⁺² orBa⁺²), the ammonium cation, as well as acid salts of organic bases,including aliphatic and aromatic substituted ammonium, and quaternaryammonium cations, such as those arising from protonation orperalkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine,pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabiclo[2.2.2]octane(DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0111] A number of the compounds of Formula I possess asymmetric carbonsand can therefore exist in racemic and optically active forms. Methodsof separation of enantiomeric and diastereomeric mixtures are well knownto one skilled in the art. The present invention encompasses anyisolated racemic or optically active form of compounds described inFormula I which possess p38 kinase inhibitory activity.

GENERAL PREPARATIVE METHODS

[0112] The compounds of Formula I may be prepared by use of knownchemical reactions and procedures, some from starting materials whichare commercially available. Nevertheless, the following generalpreparative methods are presented to aid one of skill in the art insynthesizing these compounds, with more detailed particular examplesbeing presented in the experimental section describing the workingexamples.

[0113] Nitroaryls are commonly formed by electrophilic aromaticnitration using HNO_(3,) or an alternative NO₂ ⁺ source. Nitroaryls maybe further elaborated prior to reduction. Thus, nitroaryls substitutedwith

[0114] potential leaving groups (eg. F, Cl, Br, etc.) may undergosubstitution reactions on treatment with nucleophiles, such as thiolate(exemplified in Scheme II) or phenoxide. Nitroaryls may also undergoUllman-type coupling reactions (Scheme II).

[0115] Nitroaryls may also undergo transition metal mediated crosscoupling reactions. For example, nitroaryl electrophiles, such asnitroaryl bromides, iodides or triflates, undergo palladium mediatedcross coupling reactions with aryl nucleophiles, such as arylboronicacids (Suzuki reactions, exemplified below), aryltins (Stille reactions)or arylzincs (Negishi reaction) to afford the biaryl (5).

[0116] Either nitroaryls or anilines may be converted into thecorresponding arenesulfonyl chloride (7) on treatment withchlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoridesource, such as KF then affords sulfonyl fluoride (8). Reaction ofsulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presenceof a fluoride source, such as tris(dimethylamino)sulfoniumdifluorotrimethylsiliconate (TASF) leads to the correspondingtrifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 may bereduced to the arenethiol (10), for example with zinc amalgum. Reactionof thiol 10 with CHClF₂ in the presence of base gives the difluoromethylmercaptam (11), which may be oxidized to the sulfone (12) with any of avariety of oxidants, including CrO₃-acetic anhydride (Sedova et al. Zh.Org. Khim. 1970, 6, 568).

[0117] As shown in Scheme IV, non-symmnetrical urea formation mayinvolve reaction of an aryl isocyanate (14) with an aryl amine (13). Theheteroaryl isocyanate may be synthesized from a heteroaryl amine bytreatment with phosgene or a phosgene equivalent, such astrichloromethyl chloroformate (diphosgene), bis(trichloromethyl)carbonate (triphosgene), or N,N′-carbonyldiimidazole (CDI). Theisocyanate may also be derived from a heterocyclic carboxylic acidderivative, such as an ester, an acid halide or an anhydride by aCurtius-type rearrangement. Thus, reaction of acid derivative 16 with anazide source, followed by rearrangement affords the isocyanate. Thecorresponding carboxylic acid (17) may also be subjected to Curtius-typerearrangements using diphenylphosphoryl azide (DPPA) or a similarreagent.

[0118] Finally, ureas may be further manipulated using methods familiarto those skilled in the art.

[0119] The invention also includes pharmaceutical compositions includinga compound of Formula I, and a physiologically acceptable carrier.

[0120] The compounds may be administered orally, topically,parenterally, by inhalation or spray, vaginally, rectally orsublingually in dosage unit formulations. The term ‘administration byinjection’ includes intravenous, intramuscular, subcutaneous andparenteral injections, as well as use of infusion techniques. Dermaladministration may include topical application or transdermaladministration. One or more compounds may be present in association withone or more non-toxic pharmaceutically acceptable carriers and ifdesired other active ingredients.

[0121] Compositions intended for oral use may be prepared according toany suitable method known to the art for the manufacture ofpharmaceutical compositions. Such compositions may contain one or moreagents selected from the group consisting of diluents, sweeteningagents, flavoring agents, coloring agents and preserving agents in orderto provide palatable preparations. Tablets contain the active ingredientin admixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be,for example, inert diluents, such as calcium carbonate, sodiumcarbonate, lactose, calcium phosphate or sodium phosphate; granulatingand disintegrating agents, for example, corn starch, or alginic acid;and binding agents, for example magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and adsorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. These compounds mayalso be prepared in solid, rapidly released form.

[0122] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0123] Aqueous suspensions containing the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions mayalso be used. Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolsuch as polyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives, for exampleethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

[0124] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example, sweetening, flavoring andcoloring agents, may also be present.

[0125] The compounds may also be in the form of non-aqueous liquidformulations, e.g., oily suspensions which may be formulated bysuspending the active ingredients in a vegetable oil, for examplearachis oil, olive oil, sesame oil or peanut oil, or in a mineral oilsuch as liquid paraffin. The oily suspensions may contain a thickeningagent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteningagents such as those set forth above, and flavoring agents may be addedto provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

[0126] Compounds of the invention may also be administratedtransdermally using methods known to those skilled in the art (see, forexample: Chien; “Transdermal Controlled Systemic Medications”; MarcelDekker, Inc.; 1987. Lipp et al. WO94/04157 Mar. 3, 1994). For example, asolution or suspension of a compound of Formula I in a suitable volatilesolvent optionally containing penetration enhancing agents can becombined with additional additives known to those skilled in the art,such as matrix materials and bacteriocides. After sterilization, theresulting mixture can be formulated following known procedures intodosage forms. In addition, on treatment with emulsifying agents andwater, a solution or suspension of a compound of Formula I may beformulated into a lotion or salve.

[0127] Suitable solvents for processing transdermal delivery systems areknown to those skilled in the art, and include lower alcohols such asethanol or isopropyl alcohol, lower ketones such as acetone, lowercarboxylic acid esters such as ethyl acetate, polar ethers such astetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane orbenzene, or halogenated hydrocarbons such as dichloromethane,chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitablesolvents may also include mixtures of one or more materials selectedfrom lower alcohols, lower ketones, lower carboxylic acid esters, polarethers, lower hydrocarbons, halogenated hydrocarbons.

[0128] Suitable penetration enhancing materials for transdermal deliverysystem are known to those skilled in the art, and include, for example,monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol orbenzyl alcohol, saturated or unsaturated C₈-C₁₈ fatty alcohols such aslauryl alcohol or cetyl alcohol, saturated or unsaturated C₈-C₁₈ fattyacids such as stearic acid, saturated or unsaturated fatty esters withup to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl isobutyl tertbutyl or monoglycerin esters of acetic acid,capronic acid, lauric acid, myristinic acid, stearic acid, or palmiticacid, or diesters of saturated or unsaturated dicarboxylic acids with atotal of up to 24 carbons such as diisopropyl adipate, dilsobutyladipate, diisopropyl sebacate, diisopropyl maleate, or diisopropylfumarate. Additional penetration enhancing materials includephosphatidyl derivatives such as lecithin or cephalin, terpenes, amides,ketones, ureas and their derivatives, and ethers such as dimethylisosorbid and diethyleneglycol monoethyl ether. Suitable penetrationenhancing formulations may also include mixtures of one or morematerials selected from monohydroxy or polyhydroxy alcohols, saturatedor unsaturated C₈-C₁₈ fatty alcohols, saturated or unsaturated C₈-C₁₈fatty acids, saturated or unsaturated fatty esters with up to 24carbons, diesters of saturated or unsaturated discarboxylic acids with atotal of up to 24 carbons, phosphatidyl derivatives, terpenes, amides,ketones, ureas and their derivatives, and ethers.

[0129] Suitable binding materials for transdermal delivery systems areknown to those skilled in the art and include polyacrylates, silicones,polyurethanes, block polymers, styrenebutadiene coploymers, and naturaland synthetic rubbers. Cellulose ethers, derivatized polyethylenes, andsilicates may also be used as matrix components. Additional additives,such as viscous resins or oils may be added to increase the viscosity ofthe matrix.

[0130] Pharmaceutical compositions of the invention may also be in theform of oil-in-water emulsions. The oil phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

[0131] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents.

[0132] The compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal or vaginal temperature and will therefore melt in the rectum orvagina to release the drug. Such materials include cocoa butter andpolyethylene glycols.

[0133] For all regimens of use disclosed herein for compounds of FormulaI, the daily oral dosage regimen will preferably be from 0.01 to 200mg/Kg of total body weight. The daily dosage for administration byinjection, including intravenous, intramuscular, subcutaneous andparenteral injections, and use of infusion techniques will preferably befrom 0.01 to 200 mg/Kg of total body weight. The daily vaginal dosageregimen will preferably be from 0.01 to 200 mg/Kg of total body weight.The daily rectal dosage regimen will preferably be from 0.01 to 200mg/Kg of total body weight. The transdermal concentration willpreferably be that required to maintain a daily dose of from 0.01 to 200mg/Kg. The daily topical dosage regimen will preferably be from 0.1 to200 mg administered between one to four times daily. The dailyinhalation dosage regimen will preferably be from 0.01 to 10 mg/Kg oftotal body weight.

[0134] It will be appreciated by those skilled in the art that theparticular method of administration will depend on a variety of factors,all of which are considered routinely when administering therapeutics.It will also be understood, however, that the specific dose level for agiven patient depends on a variety of factors, including specificactivity of the compound administered, the age of the patient, the bodyweight of the patient, the general health of the patient, the gender ofthe patient, the diet of the patient, time of administration, route ofadministration, rate of excretion, drug combination, and the severity ofthe condition undergoing therapy, etc. It will be further appreciated byone skilled in the art that the optimal course of treatment, i.e., themode of treatment and the daily number of doses of a compound of FormulaI or a pharmaceutically acceptable salt thereof given for a definednumber of days, can be ascertained by those skilled in the art usingconventional course of treatment tests.

[0135] The compounds of FIG. I are producible from known compounds (orfrom starting materials which, in turn, are producible from knowncompounds), e.g., through the general preparative methods shown above.The activity of a given compound to inhibit raf kinase can be routinelyassayed, e.g., according to procedures disclosed below. The followingexamples are for illustrative purposes only and are not intended, norshould they be construde to limit the invention in any way.

[0136] The entire disclosure of all applications, patents andpublications cited above and below are hereby incorporated by reference,including provisional application serial nunber attorney docket numberBayer 10-V1, filed on Dec. 22, 1997 as Ser. No. 08/995,749, andconverted on Dec. 22, 1998.

[0137] The following examples are for illustrative purposes only and arenot intended, nor should they be construed to limit the invention in anyway.

EXAMPLES

[0138] All reactions were performed in flame-dried or oven-driedglassware under a positive pressure of dry argon or dry nitrogen, andwere stirred magnetically unless otherwise indicated. Sensitive liquidsand solutions were transferred via syringe or cannula, and introducedinto reaction vessels through rubber septa. Unless otherwise stated, theterm ‘concentration under reduced pressure’ refers to use of a Buchirotary evaporator at approximately 15 mmHg.

[0139] All temperatures are reported uncorrected in degrees Celsius (°C.). Unless otherwise indicated, all parts and percentages are byweight.

[0140] Commercial grade reagents and solvents were used without furtherpurification. Thinlayer chromatography (TLC) was performed usingWhatman® pre-coated glass-backed silica gel 60A F-254 250 μm plates.Visualization of plates was effected by one or more of the followingtechniques: (a) ultraviolet illumination, (b) exposure to iodine vapor,(c) immersion of the plate in a 10% solution of phosphomolybdic acid inethanol followed by heating, (d) immersion of the plate in a ceriumsulfate solution followed by heating, and/or (e) immersion of the platein an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed byheating. Column chromatography (flash chromatography) was performedusing 230-400 mesh EM Science® silica gel.

[0141] Melting points (mp) were determined using a Thomas-Hoover meltingpoint apparatus or a Mettler FP66 automated melting point apparatus andare uncorrected. Fourier transform infrared sprectra were obtained usinga Mattson 4020 Galaxy Series spectrophotometer. Proton (¹H) nuclearmagnetic resonance (NMR) spectra were measured with a General ElectricGN-Omega 300 (300 MHz) spectrometer with either Me₄Si (d 0.00) orresidual protonated solvent (CHCl₃ δ 7.26; MeOH δ 3.30; DMSO δ 2.49) asstandard. Carbon (¹³C) NMR spectra were measured with a General ElectricGN-Omega 300 (75 MHz) spectrometer with solvent (CDCl₃ δ 77.0; MeOD-d₃;δ 49.0; DMSO-d₆ δ 39.5) as standard. Low resolution mass spectra (MS)and high resolution mass spectra (HRMS) were either obtained as electronimpact (El) mass spectra or as fast atom bombardment (FAB) mass spectra.Electron impact mass spectra (EI-MS) were obtained with a HewlettPackard 5989A mass spectrometer equipped with a Vacumetrics DesorptionChemical Ionization Probe for sample introduction. The ion source wasmaintained at 250° C. Electron impact ionization was performed withelectron energy of 70 eV and a trap current of 300 μA. Liquid-cesiumsecondary ion mass spectra (FAB-MS), an updated version of fast atombombardment were obtained using a Kratos Concept 1-H spectrometer.Chemical ionization mass spectra (CI-MS) were obtained using a HewlettPackard MS-Engine (5989A) with methane or ammonia as the reagent gas(1×10⁻⁴ torr to 2.5×10⁻⁴ torr). The direct insertion desorption chemicalionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 ampsin 10 sec and held at 10 amps until all traces of the sample disappeared(˜1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan.HPLC—electrospray mass spectra (HPLC ES-MS) were obtained using aHewlett-Packard 1100 HPLC equipped with a quaternary pump, a variablewavelength detector, a C-18 column, and a Finnigan LCQ ion trap massspectrometer with electrospray ionization. Spectra were scanned from120-800 amu using a variable ion time according to the number of ions inthe source. Gas chromatography—ion selective mass spectra (GC-MS) wereobtained with a Hewlett Packard 5890 gas chromatograph equipped with anHP-1 methyl silicone column (0.33 mM coating; 25 m×0.2 mm) and a HewlettPackard 5971 Mass Selective Detector (ionization energy 70 eV).Elemental analyses are conducted by Robertson Microlit Labs, MadisonN.J.

[0142] All compounds displayed NMR spectra, LRMS and either elementalanalysis or EMS consistant with assigned structures. List ofAbbreviations and Acronyms: AcOH acetic acid anh anhydrous BOCtert-butoxycarbonyl conc concentrated dec decomposition DMPU1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMFN,N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphorylazide EtOAc ethyl acetate EtOH ethanol (100%) Et₂O diethyl ether Et₃Ntriethylamine m-CPBA 3-chloroperoxybenzoic acid MeOH methanol pet. etherpetroleum ether (boiling range 30-60° C.) THF tetrahydrofuran TFAtrifluoroacetic acid Tf trifluoromethanesulfonyl

A. General Methods for Synthesis of Substituted Anilines A1. Synthesisof 2,5-Dioxopyrrolidinylanilines

[0143]

Step 1 4-tert-Butyl-1-(2,5-dioxo-1-pyrrolidinyl)-2-nitrobenzene

[0144] To a solution of 4-tert-butyl-2-nitroaniline (1.04 g, 5.35 mmol)in xylene (25 m ) was added succinic anhydride (0.0535 g, 5.35 mmol) andtriethylamine (0.75 mL, 5.35 mmol). The reaction mixture was heated atthe reflux temp. for 24 h, cooled to room temp. and diluted with Et₂O(25 mL). The resulting mixture was sequentially washed with a 10% HClsolution (50 mL), a saturated NH₄CL solution (50 mL) and a saturatedNaCl solution (50 mL), dried (MgSO₄), and concentrated under reducedpressure. The residue was purified by flash cromatography (60% EtOAc/40%hexane) to yield the succinimide as a yellow solid (1.2 g, 86%): mp135-138° C.; ¹H NMR (CHCl₃) δ 1.38 (s, 9H), 2.94-2.96 (m, 4H), 7.29-7.31(m, 1H), 7.74-7.78 (m, 1H), 8.18-8.19 (m, 1H).

Step 2 5-tert-Butyl-2-(2,5-dioxo-1-pyrrolidinyl)aniline

[0145] To a solution of4-tert-butyl-1-(2,5-dioxo-1-pyrrolidinyl)-2-nitrobenzene (1.1 g, 4.2mmol) in EtOAc (25 mL) was added a 10% Pd/C (0.1 g). The resultingslurry was placed under a H₂ atmosphere using 3 cycles of anevacuate-quench protocol and was allowed to stir under a H₂ atmospherefor 8 h. The reaction mixture was filtered through a pad of Celite® andthe residue was washed with CHCl₃. The combined filtrate wasconcentrated under reduced pressure to yield the desired aniline as anoff-white solid (0.75 g, 78%): mp 208-211° C.; ¹H-NMR (DMSO-d₆) δ 1.23(s, 9H), 2.62-2.76 (m, 4H), 5.10 (br s, 2H), 6.52-6,56 (m, 1H),6.67-6.70 (m, 2H).

A2. General Method for the Synthesis of Tetrahydrofuranyloxyanilines

[0146]

Step 1 4-tert-Butyl-1-(3-tetrahydrofuranyloxy)-2-nitrobenzene

[0147] To a solution of 4-tert-butyl-2-nitrophenol (1.05 g, 5.4 mmol) inanh THF (25 mL) was added 3-hydroxytetrahydrofuran (0.47 g, 5.4 mmol)and triphenylphosphine (1.55 g, 5.9 mmol) followed by diethylazodicarboxylate (0.93 ml, 5.9 mmol) and the mixture was allowed to stirat room temp. for 4 h. The resulting mixture was diluted with Et₂O (50mL) and washed with a saturated NH₄Cl solution (50 mL) and a saturatedNaCl solution (50 mL), dried (MgSO₄), and concentrated under reducedpressure. The residue was purified by flash cromatography (30% EtOAc/70%hexane) to yield the desired ether as a yellow solid (1.3 g, 91%):¹H-NMR (CHCl₃) δ 1.30 (s, 9H), 2.18-2.24 (m, 2H), 3.91-4.09 (m, 4H),5.00-5.02 (m, 1H), 6.93 (d, J=8.8 Hz, 1H), 7.52 (dd, J=2.6, 8.8 Hz, 1H),7.81 (d, J=2.6 Hz, 1H).

Step 2 5-tert-Butyl-2-(3-tetrahydrofuranyloxy)aniline

[0148] To a solution of4-tert-butyl-1-(3-tetrahydrofuranyloxy)-2-nitrobenzene (1.17 g, 4.4mmol) in EtOAc (25 mL) was added 10% Pd/C (0.1). The resulting slurrywas placed under a H₂ atmosphere using 3 cycles of an evacuate-quenchprotocol and was allowed to stir under a H₂ atmosphere for 8 h. Thereaction mixture was filtered through a pad of Celite® and washed withCHCl₃. The combined filtrate was concentrated under reduced pressure toyield of the desired aniline as a yellow solid (0.89 g, 86%): mp 79-82°C.; ¹H-NMR (CHCl₃) δ1.30 (s, 9H), 2.16-2.20 (m, 2H), 3.78 (br s, 2H),3.85-4.10 (m, 4H),4.90 (m, 1H), 6.65-6.82 (m, 3H).

A3. General Method for the Synthesis of Trifluoromethanesulfonylanilines

[0149]

Step 1 2-Methoxy-5-(fluorosulfonyl)acetanilide

[0150] Acetic anhydride (0.90 mL, 9.6 mmol) was added to a solution of4-methoxymetanilyl fluoride (1.0 g, 4.8 mmol) in pyridine (15 mL). Afterbeing stirred at room temp. for 4 h, the reaction mixture wasconcentrated under reduced pressure. The resulting residue was dissolvedin CH₂Cl₂ (25 mL), washed with a saturated NaHCO₃ solution (25 mL),dried (Na₂SO₄), and concentrated under reduced pressure to give a foamwhich was triturated with a Et₂O/hexane solution to provide the titlecompound (0.85 g): ¹H-NMR (CDCl₃) δ 2.13 (s, 3H), 3.98 (s, 3H), 7.36 (d,J=8.5 Hz, 1H), 7.82 (dd, J=2.6, 8.8 Hz, 1H), 8.79 (d, J=2.2 Hz, 1H),9.62 (br s, 1H).

Step 2 2-Methoxy-5-(trifluoromethanesulfonyl)acetanilide

[0151] To an ice-cooled suspension of tris(dimethylamino)sulfoniumdifluorotrimethylsiliconate (0.094 g, 0.34 mmol) in THF (4 mL) was addeda solution of (trifluoromethyl)trimethylsilane (1.0 mL, 6.88 mmol) inTHF (3 mL) followed by a solution of2-methoxy-5-(fluorosulfonyl)acetanilide (0.85 g, 3.44 mmol) in THF (3mL). The reaction mixture was stirred for 2 h on an ice bath, then wasallowed to warm to room temp. and was then concentrated under reducedpressure. The resulting residue was dissolved in CH₂Cl₂ (25 mL), washedwith water (25 mL), dried (Na₂SO₄), and concentrated under reducedpressure. The resulting material was purified by flash chromatography(3% MeOH/97% CH₂Cl₂) to provide the title compound as a white solid(0.62 g): ¹H-NMR (CDCl₃) δ 2.13 (s, 3H) 4.00 (s, 3H), 7.42 (d, J=8.8 Hz,1H), 7.81 (dd, J=2.6, 8.8 Hz, 1H), 8.80 (d, J=2.2 Hz, 1H), 9.64 (br s,1H); FAB-MS m/z 298 ((M+1)⁺).

Step 3 2-Methoxy-5-(trifluoromethanesulfonyl)aniline

[0152] A solution of 2-methoxy-5-trifluoromethanesulfonyl)acetanilide(0.517 g, 1.74 mmol) in EtOH (5 mL) and a 1 N HCl solution (5 mL) washeated at the reflux temp. for 4 h and the resulting mixture wasconcentrated under reduced pressure. The residue was dissolved in CH₂Cl₂(30 mL), washed with water (30 mL), dried (Na₂SO₄), and concentratedunder reduced pressure to afford the title compound as a gum (0.33 g):¹H-NMR (CDCl₃) δ 3.90 (s, 3H) 5.57 (br s, 2H), 7.11-7.27 (m, 3H); FAB-MSm/z 256 ((M+1)⁺). This material was used in urea formation withoutfurther purification.

A4. General Method for Aryl Amine Formation via Phenol NitrationFollowed by Ether Formation and Reduction

[0153]

Step 1 2-Nitro-5-tert-butylphenol

[0154] A mixture of fuming nitric acid (3.24 g, 77.1 mmol) in glacialHOAc (10 mL) was added dropwise to a solution of m-tert-butylphenol(11.58 g, 77.1 mmol) in glacial HOAc (15 mL) at 0° C. The mixture wasallowed to stir at 0° C. for 15 min then warmed to room temp. After 1 hthe mixture was poured into ice water (100 mL) and extracted with Et₂O(2×50 mL). The organic layer was washed with a saturated NaCl solution(100 mL), dried (MgSO₄) and concentrated in vacuo. The residue waspurified by flash chromatography (30% EtOAc/70% hexane) to give thedesired phenol (4.60 g, 31%): ¹H-NMR (DMSO-d₆) δ 1.23 (s, 9H), 7.00 (dd,J=1.84, 8.83, Hz, 1H), 7.07 (d, J=1.84 Hz, 1H), 7.82 (d, J=8.83 Hz, 1H),10.74 (s, 1H).

Step 2 2-Nitro-5-tert-butylanisole

[0155] A slurry of 2-nitro-5-tert-butylphenol (3.68 g, 18.9 mmol) andK₂CO₃ (3.26 g, 23.6 mmol) in anh DMF (100 mL) was stirred at room tempwith stirring for 15 min then treated with iodomethane (2.80 g, 19.8mmol) via syringe. The reaction was allowed to stir at room temp for 18h., then was treated with water (100 mL) and extracted with EtOAc (2×100mL). The combined organic layers were washed with a saturated NaClsolution (50 mL), dried (MgSO₄) and concentrated in vacuo to give thedesired ether (3.95 g, 100%): ¹H-NMR (DMSO-d₆) δ 1.29 (s, 9H), 3.92 (s,3H), 7.10 (dd, J=1.84, 8.46 Hz, 1H), 7.22 (d, J=1.84 Hz, 1H), 7.79 (d,J=8.46 Hz, 1H). This material was used in the next step without furtherpurification.

Step 3 4-tert-Butyl-2-methoxyaniline

[0156] A solution of 2-nitro-5-tert-butylanisole (3.95 g, 18.9 mmol) inMeOH (65 mL) and added to a flask containing 10% Pd/C in MeOH (0.400 g),then placed under a H₂ atmosphere (balloon). The reaction was allowed tostir for 18 h at room temp, then filtered through a pad of Celite® andconcentrated in vacuo to afford the desired product as a dark sitckysolid (3.40 g, 99%): ¹H-NMR (DMSO-d₆) δ 1.20 (s, 9H), 3.72 (s, 3H), 4.43(br s, 2H), 6.51 (d, J=8.09 Hz, 1H), 6.64 (dd, J=2.21, 8.09 Hz, 1H),6.76 (d, J=2.21 Hz, 1H).

A5. General Method for Aryl Amine Formation via Carboxylic AcidEsterification Followed by Reduction

[0157]

Step 1 Methyl 2-Nitro-4-(trifluoromethyl)benzoate

[0158] To a solution of 2-nitro-4-(trifluoromethyl)benzoic acid (4.0 g,17.0 mmol) in MeOH (150 mL) at room temp was added conc H₂SO₄ (2.5 mL).The mixture was heated at the reflux temp for 24 h., cooled to room tempand concentrated in vacuo. The residue was diluted with water (100 mL)and extracted with EtOAc (2×100 mL). The combined organic layers werewashed with a saturated NaCl solution, dried (MgSO₄), concentrated invacuo. The residue was purified by flash chromatography (14% EtOAc/86%hexane) to give the desired ester as a pale yellow oil (4.17 g, 98%):¹H-NMR (DMSO-d₆) δ 3.87 (s, 3H), 8.09 (d, J=7.72 Hz, 1H), 8.25 (dd,J=1.11, 8.09 Hz, 1H), 8.48 (d,J=1.11 Hz, 1H).

Step 2 Methyl 2-Amino-4-(trifluoromethyl)benzoate

[0159] A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate (3.90 g,15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10% Pd/C(0.400 mg) in EtOAc (10 mL), then placed under a H₂ atmosphere(balloon). The reaction was allowed to stir for 18 h at room temp, thenwas filtered through Celite® and concentrated in vacuo to afford thedesired product as a white crystalline solid (3.20 g, 93%): ¹H-NMR(DMSO-d₆) δ 3.79 (s, 3H), 6.75 (dd, J=1.84, 8.46 Hz, 1H), 6.96 (br s,2H), 7.11 (d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).

A6. General Method for Aryl Amine Formation via Ether Formation FollowedEster Saponification, Curtius Rearrangement, and Carbamate Deprotection

[0160]

Step 1 Methyl 3-Methoxy-2-naphthoate

[0161] A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) andK₂CO₃ (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temp for15 min, then treated with iodomethane (3.43 mL, 55.1 mmol). The mixturewas allowed to stir at room temp overnight, then was treated with water(200 mL). The resulting mixture was extracted with EtOAc (2×200 mL). Thecombined organic layers were washed with a saturated NaCl solution (100mL), dried (MgSO₄), concentrated in vacuo (approximately 0.4 mmHgovernight) to give the desired ether as an amber oil (10.30 g): ¹H-NMR(DMSO-d₆) δ 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J=8.09 Hz, 1H),7.44 (s, 1H), 7.53 (app t, J=8.09 Hz, 1H), 7.84 (d, J=8.09 Hz, 1H), 7.90(s, 1H), 8.21 (s, 1H).

Step 2 3-Methoxy-2-naphthoic Acid

[0162] A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol)and water (10 mL) in MeOH (100 mL) at room temp was treated with a 1 NNaOH solution (33.4 mL, 33.4 mmol). The mixture was heated at the refluxtemp for 3 h, cooling to room temp, and made acidic with a 10% citricacid solution. The resulting solution was extracted with EtOAc (2×100mL). The combined organic layers were washed with a saturated NaClsolution, dried (MgSO₄) and concentrated in vacuo. The residue wastriturated with hexanes and washed several times with hexanes to givethe desired carboxylic acid as a white crystalline solid (5.40 g, 92%):¹H-NMR (DMSO-d₆) δ 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H),7.83 (d, J=8.09 Hz, 1H), 7.91 (d, J=8.09 Hz, 1H), 8.19 (s, 1H), 12.83(br s, 1H).

Step 3 2-(N-(Carbobenzyloxy)amino-3-methoxynaphthalene

[0163] A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) andEt₃N (2.59 mL, 18.6 mmol) in anh toluene (70 mL) was stirred at roomtemp. for 15 min., then treated with a solution of diphenylphosphorylazide (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The resultingmixture was heated at 80° C. for 2 h. After cooling the mixture to roomtemp. benzyl alcohol (2.06 mL, 20 mmol) was added via syringe. Themixture was then warmed to 80° C. overnight. The resulting mixture wascooled to room temp., quenched with a 10% citric acid solution, andextracted with EtOAc (2×100 mL). The combined organic layers were washedwith a saturated NaCl solution, dried (MgSO₄), and concentrated invacuo. The residue was purified by flash chromatography (14% EtOAc/86%hexane) to give the benzyl carbamate as a pale yellow oil (5.1 g, 100%):¹H-NMR (DMSO-d₆) δ 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H),7.72-7.75 (m, 2H), 8.20 (s, 1H), 8.76 (s, 1H).

Step 4 2-Amino-3-methoxynaphthalene

[0164] A slurry of 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0g, 16.3 mmol) and 10% Pd/C (0.5 g) in EtOAc (70 mL) was maintained undera H₂ atmospheric (balloon) at room temp. overnight. The resultingmixture was filtered through Celite® and concentrated in vacuo to givethe desired amine as a pale pink powder (2.40 g, 85%): ¹H-NMR (DMSO-d₆)δ 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, J=8.0 Hz, 1H),7.56 (d, J=8.0 Hz, 1H); EI-MS m/z 173 (M³⁰ ).

A7. General Method for the Synthesis of Aryl Amines via Metal-MediatedCross Coupling Followed by Reduction

[0165]

Step 1 5-tert-Butyl-2-(trifluoromethanesulfonyl)oxy-1-nitrobenzene

[0166] To an ice cold solution of 4-tert-butyl-2-nitrophenol (6.14 g,31.5 mmol) and pyridine (10 mL, 125 mmnol) in CH₂Cl₂ (50 mL) was slowlyadded trifluoromethanesulfonic anhydride (10 g, 35.5 mmol) via syringe.The reaction mixture was stirred for 15 min, then allowed to warm up toroom temp. and diluted with CH₂Cl₂ (100 mL). The resulting mixture wassequentially washed with a 1M NaOH solution (3×100 mL), and a 1M HClsolution (3×100 mL), dried (MgSO₄), and concentrated under reducedpressure to afford the title compound (8.68 g, 84%): ¹H-NMR (CDCl₃) δ1.39 (s, 9H), 7.30-8.20 (m, 3H).

Step 2 5-tert-Butyl-2-(3-fluorophenyl)-1-nitrobenzene

[0167] A mixture of 3-fluorobenzeneboronic acid (3.80 g, 27.5 mmol), KBr(2.43 g, 20.4 mmol), K₃PO₄ (6.1 g, 28.8 mmol), and Pd(PPh₃)₄ (1.0 g, 0.9mmol) was added to a solution of5-tert-butyl-2-(trifluoromethanesulfonyl)oxy-1-nitrobenzene (6.0 g, 18.4mmol) in dioxane (100 mL). The reaction mixture was heated at 80° C. for24 h, at which time TLC indicated complete reaction. The reactionmixture was treated with a saturated NH₄Cl solution (50 mL) andextracted EtOAc (3×100 mL). The combined organic layers were dried(MgSO₄) and concentrated under reduced pressure. The residue waspurified by flash chromatography (3% EtOAc/97% hexane) to give the titlecompound (4.07 g, 81%): ¹H-NMR (CDCl₃) δ 1.40 (s, 9H), 6.90-7.90 (m,7H).

Step 3 5-tert-Butyl-2-(3-fluorophenyl)aniline

[0168] To a solution of 5-tert-butyl-2-(3-fluorophenyl)-1-nitrobenzene(3.5 g, 12.8 mmol) and EtOH (24 mL) in EtOAc (96 mL) was added 5% Pd/C(0.350 g) and the resulting slurry was stirred under a H₂ atmosphere for24 h, at which time TLC indicated complete consumption of startingmaterial. The reaction mixture was filtered through a pad of Celite® togive the desired product (2.2 g, 72%): ¹H-NMR (CDCl₃) δ 1.35 (s, 9H),3.80 (br s, 2H), 6.90-7.50 (m, 7H).

A8. General Method for the Synthesis of Nitroanilines

[0169]

Step 1 4-(4-(2-Propoxycarbonylamino)phenyl)methylaniline

[0170] A solution of di-tert-butyl dicarbonate (2.0 g, 9.2 mmol) and4,4′-methylenedianiline (1.8 g, 9.2 mmol) in DMF (100 mL) was heated atthe reflux temp. for 2 h, then cooled to room temp. This mixture wasdiluted with EtOAc (200 mL) sequentially washed with a saturated NH₄Cl(200 mL) and a saturated NaCl solution (100 mL), and dried (MgSO₄). Theresidue was purified by flash chromatography (30% EtOAc/70% hexane) togive the desired carbamate (1.3 g, 48%): ¹H-NMR (CDCl₃) δ 1.51 (s, 9H),3.82 (s, 2H), 6.60-7.20 (m, 8H).

Step 2 4-(4-(2-Propoxycarbonylamino)phenyl)methyl-1-nitrobenzene

[0171] To an ice cold solution of4-(4-(2-propoxycarbonylamino)phenyl)methylaniline (1.05 g, 3.5 mmol) inCH₂Cl₂ (15 mL) was added m-CPBA (1.2 g, 7.0 mmol). The reaction mixturewas slowly allowed to warm to room temp. and was stirred for 45 min, atwhich time TLC indicated disappearance of starting material. Theresulting mixture was diluted with EtOAc (50 mL), sequentially washedwith a 1M NaOH solution (50 mL) and a saturated NaCl solution (50 mL),and dried (MgSO₄). The residue was purified by flash chromatography (20%EtOAc/80% hexane) to give the desired nitrobenzene (0.920 g): FAB-MS m/z328 (M⁺).

Step 3 4-(4-Nitrophenyl)methylaniline

[0172] To a solution of4-(4-(2-propoxycarbonylamino)phenyl)methyl-1-nitrobenzene (0.920 g, 2.8mmol) in dioxane (10 mL) was added a conc. HCl solution (4.0 mL) and theresulting mixture was heated at 80° C. for 1 h at which time TLCindicated disappearance of starting material. The reaction mixture wascooled to room temp. The resulting mixture was diluted with EtOAc (50mL), then washed with a 1M NaOH solution (3×50 mL), and dried (MgSO₄) togive the desired aniline (0.570 mg, 89%): ¹H-NMR (CDCl₃) δ 3.70 (br s,2H), 3.97 (s, 2H), 6.65 (d, J=8.5 Hz, 2H), 6.95 (d, J=8.5 Hz, 2H), 7.32(d, J=8.8 Hz, 2H), 8.10 (d, J=8.8 Hz, 2H).

A9. General Method for Synthesis of Aryl Anilines via Alkylation of aNitrophenol Followed by Reduction

[0173]

Step 1 4-(α-Bromoacetyl)morpholine

[0174] To an ice cold solution of morpholine (2.17 g, 24.9 mmol) anddiisopropylethylamine (3.21 g, 24.9 mmol) in CH₂Cl₂ (70 mL) was added asolution of bromoacetyl bromide (5.05 g, 25 mmole) in CH₂Cl₂ (8 mL) viasyringe. The resulting solution was kept at 0° C. for 45 min, then wasallowed to warm to room temp. The reaction mixture was diluted withEtOAc (500 mL), sequentially washed with a 1M HCl solution (250 mL) anda saturated NaCl solution (250 mL), and dried (MgSO₄) to give thedesired product (3.2 g, 62%): ¹H-NMR (DMSO-d₆) δ 3.40-3.50 (m, 4H),3.50-3.60 (m, 4H), 4.11 (s, 2H).

Step 2 2-(N-Morpholinylcarbonyl)methoxy-5-tert-butyl-1-nitrobenzene

[0175] A slurry of 4-tert-butyl-2-nitrophenol (3.9 g, 20 mmol) and K₂CO₃(3.31 g, 24 mmol) in DMF (75 mL) was stirred at room temp. for 15minutes, then a solution of 4-(α-bromoacetyl)morpholine (4.16 g, 20mmol) in DMF (10 mL) was added. The reaction was allowed to stir at roomtemp. overnight, then was diluted with EtOAc (500 mL) and sequentiallywashed with a saturated NaCl solution (4×200 mL) and a 1M NaOH solution(400 mL). The residue was purified by flash chromatography (75%EtOAc/25% hexane) to give the nitrobenzene (2.13 g, 33%): ¹H-NMR(DMSO-d₆) δ 1.25 (s, 9H), 3.35-3.45 (m, 4H), 3.50-3.58 (m, 4H), 5.00 (s,2H), 7.12 (d, J=8.8 Hz, 1H), 7.50-7.80 (m, 2H).

Step 3 2-(N-Morpholinylcarbonyl)methoxy-5-tert-butylaniline

[0176] To a solution of2-(N-morpholinylcarbonyl)methoxy-5-tert-butyl-1-nitrobenzene(2.13 g, 6.6mmol) and EtOH (10 mL) in EtOAc (40 mL) was added 5% Pd/C (0.215 g). Theresulting slurry was stirred under a H₂ atmosphere for 6 h, at whichtime TLC indicated complete consumption of starting material. Thereaction mixture was filtered through a pad of Celite® to give thedesired product (1.9 g, 98%): ¹H-NMR (DMSO-d₆) δ 1.18 (s, 9H), 3.40-3.50(m, 4H), 3.50-3.60 (m, 4H), 4.67 (br s, 2H), 4.69 (s, 2H), 6.40-6.70 (m,3H)

A10. General Method for Aryl Amine Formation via Nitrophenol AlkylationFollowed by Reduction

[0177]

Step 1 5-tert-Butyl-2-(2-hydroxyethoxy)-1-nitrobenzene

[0178] A solution of 4-tert-butyl-2-nitrophenol (30 g, 0.15 mol) andtetra-n-butylammonium fluoride (0.771 g, 3.0 mmol) in ethylene carbonate(10.24 mL. 0.15 mol) was heated at 150° C. for 18 h, then cooled to roomtemp. and separated between water (50 mL) and CH₂Cl₂ (50 mL). Theorganic layer was dried (MgSO₄) and concentrated under reduced pressure.The residue was purified by column chromatography (20% EtOAc/80% hexane)to afford the desired product as a brown oil (35.1 g, 90%): ¹H-NMR(DMSO-d₆) δ 1.25 (s, 9H), 3.66-3.69 (m, 2H), 4.10-4.14 (t, J=5.0 Hz,2H), 4.85 (t, J=5.0 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.60-7.64 (m, 1H),7.75 (d, J=2.6 Hz, 1H).

Step 2 5-tert-Butyl-2-(2-tert-butoxycarbonyloxy)ethoxy)-1-nitrobenzene

[0179] A solution of 5-tert-butyl-2-(2-hydroxyethoxy)-1-nitrobenzene(0.401 g, 1.68 mmol), di-tert-butyl dicarbonate (0.46 mL, 2.0 mmol) anddimethylaminopyridine (0.006 g, 0.05 mmol) in CH₂Cl₂ (15 mL) was stirredat room temp. for 30 min, at which time TLC indicated consumption ofstarting material. The resulting mixture was washed with water (20 mL),dried (MgSO₄) and concentrated under reduced pressure. The residue waspurified by column chromatography (3% MeOH/97% CH₂Cl₂) to give thedesired product as a yellow oil (0.291 g, 51%): ¹H-NMR (DMSO-d₆) δ 1.25(s, 9H), 1.38 (s, 9H), 4.31 (br s, 4H), 7.27 (d, J=9.2 Hz, 1H) 7.64 (dd,J=2.6, 8.8 Hz, 1H) 7.77 (d, J=2.6 Hz, 1H).

Step 3 5-tert-Butyl-2-(2-tert-butoxycarbonyloxy)ethoxy)aniline

[0180] To a mixture of5-tert-butyl-2-(2-tert-butoxycarbonyloxy)ethoxy)1-nitrobenzene (0.290 g,0.86 mmol) and 5% Pd/C (0.058 g) in MeOH (2 mL) was ammonium formate(0.216 g, 3.42 mmol), and the resulting mixture was stirred at roomtemp. for 12 h, then was filtered through a pad of Celite® with the aidof EtOH. The filtrate was concentrated under reduced pressure and theresidue was purified by column chromatography (2% MeOH/98% CH₂Cl₂) tpgive the desired product as a pale yellow oil (0.232 g, 87%): TLC (20%EtOAc/80% hexane) R_(ƒ) 0.63; ¹H-NMR (DMSO-d₆) δ 1.17 (s, 9H), 1.39 (s,9H), 4.03-4.06 (m, 2H), 4.30-4.31 (m, 2H), 4.54 (br s, 2H), 6.47 (dd,J=2.2, 8.1 Hz, 1H) 6.64-6.67 (m, 2H).

A11. General Method for Substituted Aniline Formation via Hydrogenationof a Nitroarene

[0181]

4-(4-Pyridinylmethyl)aniline

[0182] To a solution of 4-(4-nitrobenzyl)pyridine (7.0 g, 32.68 mmol) inEtOH (200 mL) was added 10% Pd/C (0.7 g) and the resulting slurry wasshaken under a H₂ atmosphere (50 psi) using a Parr shaker. After 1 h,TLC and ¹H-NMR of an aliquot indicated complete reaction. The mixturewas filtered through a short pad of Celite®. The filtrate wasconcentrated in vacuo to afford a white solid (5.4 g, 90%): ¹H-NMR(DMSO-d₆) δ 3.74 (s, 2H), 4.91 (br s, 2H), 6.48 (d, J=8.46 Hz, 2H), 6.86(d, J=8.09 Hz, 2H), 7.16 (d, J=5.88 Hz, 2H), 8.40 (d, J=5.88 Hz, 2H);EI-MS m/z 184 (M⁺). This material was used in urea formation reactionswithout further purification.

A12. General Method for Substituted Aniline Formation via DissolvingMetal Reduction of a Nitroarene

[0183]

4-(2-Pyridinylthio)aniline

[0184] To a solution of 4-(2-pyridinylthio)-1-nitrobenzene (Menai ST3355A; 0.220 g, 0.95 mmol) and H₂O (0.5 mL) in AcOH (5 mL) was addediron powder (0.317 g, 5.68 mmol) and the resulting slurry stirred for 16h at room temp. The reaction mixture was diluted with EtOAc (75 mL) andH₂O (50 mL), basified to pH 10 by adding solid K₂CO₃ in portions(Caution: foaming). The organic layer was washed with a saturated NaClsolution, dried (MgSO₄), concentrated in vacuo. The residual solid waspurified by MPLC (30% EtOAc/70% hexane) to give the desired product as athick oil (0.135 g, 70%): TLC (30% EtOAc/70% hexanes) R_(ƒ) 0.20.

A13a. General Method for Substituted Aniline Formation via NitroareneFormation Through Nucleophilic Aromatic Substitution, Followed byReduction

[0185]

Step 1 1-Methoxy-4-(4-nitrophenoxy)benzene

[0186] To a suspension of NaH (95%, 1.50 g, 59 mmol) in DMF (100 mL) atroom temp. was added dropwise a solution of 4-methoxyphenol (7.39 g, 59mmol) in DMF (50 mL). The reaction was stirred 1 h, then a solution of1-fluoro-4-nitrobenzene (7.0 g, 49 mmol) in DMF (50 mL) was addeddropwise to form a dark green solution. The reaction was heated at 95°C. overnight, then cooled to room temp., quenched with H₂O, andconcentrated in vacuo. The residue was partitioned between EtOAc (200mL) and H₂O (200 mL) . The organic layer was sequentially washed withH₂O (2×200 mL), a saturated NaHCO₃ solution (200 mL), and a saturatedNaCl solution (200 mL), dried (Na₂SO₄), and concentrated in vacuo. Theresidue was triturated (Et₂O/hexane) to afford1-methoxy-4-(4-nitrophenoxy)benzene (12.2 g, 100%): ¹H-NMR (CDCl₃) δ3.83 (s, 3H), 6.93-7.04 (m, 6H), 8.18 (d, J=9.2 Hz, 2H); EI-MS m/z 245(M⁺).

Step 2 4-(4-Methoxyphenoxy)aniline

[0187] To a solution of 1-methoxy-4-(4-nitrophenoxy)benzene (12.0 g, 49mmol) in EtOAc (250 mL) was added 5% Pt/C (1.5 g) and the resultingslurry was shaken under a H₂ atmosphere (50 psi) for 18 h. The reactionmixture was filtered through a pad of Celite® with the aid of EtOAc andconcentrated in vacuo to give an oil which slowly solidified (10.6 g,100%): ¹H-NMR (CDCl₃) δ 3.54 (br s, 2H), 3.78 (s, 3H), 6.65 (d, J=8.8Hz, 2H), 6.79-6.92 (m, 6H); EI-MS m/z 215 (M⁺).

A13b. General Method for Substituted Aniline Formation via NitroareneFormation Through Nucleophilic Aromatic Substitution, Followed byReduction

[0188]

Step 1 3-(Trifluoromethyl)-4-(4-pyridinylthio)nitrobenzene

[0189] A solution of 4-mercaptopyridine (2.8 g, 24 mmoles),2-fluoro-5-nitrobenzotrifluoride (5 g, 23.5 mmoles), and potassiumcarbonate (6.1 g, 44.3 mmoles) in anhydrous DMF (80 mL) was stirred atroom temperature and under argon overnight. TLC showed completereaction. The mixture was diluted with Et₂O (100 mL) and water (100 mL)and the aqueous layer was back-extracted with Et₂O (2×100 mL). Theorganic layers were washed with a saturated NaCl solution (100 mL),dried (MgSO₄), and concentrated under reduced pressure. The solidresidue was triturated with Et₂O to afford the desired product as a tansolid (3.8 g, 54%): TLC (30% EtOAc/70% hexane) R_(ƒ) 0.06; ¹H-NMR(DMSO-d₆) δ 7.33 (dd, J=1.2, 4.2 Hz, 2H), 7.78 (d, J=8.7 Hz, 1H), 8.46(dd, J=2.4, 8.7 Hz, 1H), 8.54-8.56 (m, 3H).

Step 2 3-(Trifluoromethyl)-4-(4-pyridinylthio)aniline

[0190] A slurry of 3-trifluoromethyl-4-(4-pyridinylthio)nitrobenzene(3.8 g, 12.7 mmol), iron powder (4.0 g, 71.6 mmol), acetic acid (100mL), and water (1 mL) were stirred at room temp. for 4 h. The mixturewas diluted with Et₂O (100 mL) and water (100 mL). The aqueous phase wasadjusted to pH 4 with a 4 N NaOH solution. The combined organic layerswere washed with a saturated NaCl solution (100 mL), dried (MgSO₄), andconcentrated under reduced pressure. The residue was filtered through apad of silica (gradient from 50% EtOAc/50% hexane to 60% EtOAc/40%hexane) to afford the desired product (3.3 g): TLC (50% EtOAc/50%hexane) R_(ƒ) 0.10; ¹H-NMR (DMSO-d₆) δ 6.21 (s, 2H), 6.84-6.87 (m, 3H),7.10 (d, J=2.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 8.29 (d, J=6.3 Hz, 2H).

A13c. General Method for Substituted Aniline Formation via NitroareneFormation Through Nucleophilic Aromatic Substitution, Followed byReduction

[0191]

Step 1 4-(2-(4-Phenyl)thiazolyl)thio-1-nitrobenzene

[0192] A solution of 2-mercapto-4-phenylthiazole (4.0 g, 20.7 mmoles) inDMF (40 mL) was treated with 1-fluoro-4-nitrobenzene (2.3 mL, 21.7mmoles) followed by K₂CO₃ (3.18 g, 23 mmol), and the mixture was heatedat approximately 65° C. overnight. The reaction mixture was then dilutedwith EtOAc (100 mL), sequentially washed with water (100 mL) and asaturated NaCl solution (100 mL), dried (MgSO₄) and concentrated underreduced pressure. The solid residue was triturated with a Et₂O/hexanesolution to afford the desired product (6.1 g): TLC (25% EtOAc/75%hexane) R_(ƒ) 0.49; ¹H-NMR (CDCl₃) δ 7.35-7.47 (m, 3H), 7.58-7.63 (m,3H), 7.90 (d, J=6.9 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H).

Step 2 4-(2-(4-Phenyl)thiazolyl)thioaniline

[0193] 4-(2-(4-Phenyl)thiazolyl)thio-1-nitro-benzene was reduced in amanner analagous to that used in the preparation of3-(trifluoromethyl)-4-(4-pyridinylthio)aniline: TLC (25% EtOAc/75%hexane) R_(ƒ) 0.18; ¹H-NMR (CDCl₃) δ 3.89 (br s, 2H), 6.72-6.77 (m, 2H),7.26-7.53 (m, 6H), 7.85-7.89 (m, 2H).

A13d. General Method for Substituted Aniline Formation via NitroareneFormation Through Nucleophilic Aromatic Substitution, Followed byReduction

[0194]

Step 1 4-(6-Methyl-3-pyridinyloxy)-1-nitrobenzene

[0195] To a solution of 5-hydroxy-2-methylpyridine (5.0 g, 45.8 mmol)and 1-fluoro-4-nitrobenzene (6.5 g, 45.8 mmol) in anh DMF (50 mL) wasadded K₂CO₃ (13.0 g, 91.6 mmol) in one portion. The mixture was heatedat the reflux temp. with stirring for 18 h and then allowed to cool toroom temp. The resulting mixture was poured into water (200 mL) andextracted with EtOAc (3×150 mL). The combined organics were sequentiallywashed with water (3×100 mL) and a saturated NaCl solution (2×100 mL),dried (Na₂SO₄), and concentrated in vacuo to afford the desired product(8.7 g, 83%). The this material was carried to the next step withoutfurther purification.

Step 2 4-(6-Methyl-3-pyridinyloxy)aniline

[0196] A solution of 4-(6-methyl-3-pyridinyloxy)-1-nitrobenzene (4.0 g,17.3 mmol) in EtOAc (150 mL) was added to 10% Pd/C (0.500 g, 0.47 mmol)and the resulting mixture was placed under a H₂ atmosphere (balloon) andwas allowed to stir for 18 h at room temp. The mixture was then filteredthrough a pad of Celite® and concentrated in vacuo to afford the desiredproduct as a tan solid (3.2 g, 92%): EI-MS m/z 200 (M⁺).

A13e. General Method for Substituted Aniline Formation via NitroareneFormation Through Nucleophilic Aromatic Substitution, Followed byReduction

[0197]

Step 1 4-(3,4-Dimethoxyphenoxy)-1-nitrobenzene

[0198] To a solution of 3,4-dimethoxyphenol (1.0 g, 6.4 mmol) and1-fluoro-4-nitrobenzene (700 μL, 6.4 mmol) in anh DMF (20 mL) was addedK₂CO₃ (1.8 g, 12.9 mmol) in one portion. The mixture was heated at thereflux temp with stirring for 18 h and then allowed to cool to roomtemp. The mixture was then poured into water (100 mL) and extracted withEtOAc (3×100 mL). The combined organics were sequentially washed withwater (3×50 mL) and a saturated NaCl solution (2×50 mL), dried (Na₂SO₄),and concentrated in vacuo to afford the desired product (0.8 g, 54%).The crude product was carried to the next step without furtherpurification.

Step 2 4-(3,4-Dimethoxyphenoxy)aniline

[0199] A solution of 4-(3,4-dimethoxy-phenoxy)-1-nitrobenzene (0.8 g,3.2 mmol) in EtOAc (50 mL) was added to 10% Pd/C (0.100 g) and theresulting mixture was placed under a H₂ atmosphere (balloon) and wasallowed to stir for 18 h at room temp. The mixture was then filteredthrough a pad of Celite® and concentrated in vacuo to afford the desiredproduct as a white solid (0.6 g, 75%): EI-MS m/z 245 (M⁺).

A13f. General Method for Substituted Aniline Formation via NitroareneFormation Through Nucleophilic Aromatic Substitution, Followed byReduction

[0200]

Step 1 3-(3-Pyridinyloxy)-1-nitrobenzene

[0201] To a solution of 3-hydroxypyridine (2.8 g, 29.0 mmol),1-bromo-3-nitrobenzene (5.9 g, 29.0 mmol) and copper(I) bromide (5.0 g,34.8 mmol) in anh DMF (50 mL) was added K₂CO₃ (8.0 g, 58.1 mmol) in oneportion. The resulting mixture was heated at the reflux temp. withstirring for 18 h and then allowed to cool to room temp. The mixture wasthen poured into water (200 mL) and extracted with EtOAc (3×150 mL). Thecombined organics were sequentially washed with water (3×100 mL) and asaturated NaCl solution (2×100 mL), dried (Na₂SO₄), and concentrated invacuo. The resulting oil was purified by flash chromatography (30%EtOAc/70% hexane) to afford the desired product (2.0 g, 32%). Thismaterial was used in the next step without further purification.

Step 2 3-(3-Pyridinyloxy)aniline

[0202] A solution of 3-(3-pyridinyloxy)-1-nitrobenzene (2.0 g, 9.2 mmol)in EtOAc (100 mL) was added to 10% Pd/C (0.200 g) and the resultingmixture was placed under a H₂ atmosphere (balloon) and was allowed tostir for 18 h at room temp. The mixture was then filtered through a padof Celite® and concentrated in vacuo to afford the desired product as ared oil (1.6 g, 94%): EI-MS m/z 186 (M⁺).

A13g. General Method for Substituted Aniline Formation via NitroareneFormation Through Nucleophilic Aromatic Substitution, Followed byReduction

[0203]

Step 1. 3-(5-Methyl-3-pyridinyloxy)-1-nitrobenzene

[0204] To a solution of 3-hydroxy-5-methylpyridine (5.0 g, 45.8 mmol),1-bromo-3-nitrobenzene (12.0 g, 59.6 mmol) and copper(I) iodide (10.0 g,73.3 mmol) in anh DMF (50 mL) was added K₂CO₃ (13.0 g, 91.6 mmol) in oneportion. The mixture was heated at the reflux temp. with stirring for 18h and then allowed to cool to room temp. The mixture was then pouredinto water (200 mL) and extracted with EtOAc (3×150 mL). The combinedorganics were sequentially washed with water (3×100 mL) and a saturatedNaCl solution (2×100 mL), dried (Na₂SO₄), and concentrated in vacuo .The resulting oil was purified by flash chromatography (30% EtOAc/70%hexane) to afford the desired product (1.2 g, 13%).

Step 2. 3-(5-Methyl-3-pyridinyloxy)-1-nitrobenzene

[0205] A solution of 3-(5-methyl-3-pyridinyloxy)-1-nitrobenzene (1.2 g,5.2 mmol) in EtOAc (50 mL) was added to 10% Pd/C (0.100 g) and theresulting mixture was placed under a H₂ atmosphere (balloon) and wasallowed to stir for 18 h at room temp. The mixture was then filteredthrough a pad of Celite® and concentrated in vacuo to afford the desiredproduct as a red oil (0.9 g, 86%): CI-MS m/z 201 ((M+H)⁺).

A13h. General Method for Substituted Aniline Formation via NitroareneFormation Through Nucleophilic Aromatic Substitution, Followed byReduction

[0206]

Step 1. 5-Nitro-2-(4-methylphenoxy)pyridine

[0207] To a solution of 2-chloro-5-nitropyridine (6.34 g, 40 mmol) inDMF (200 mL) were added of 4-methylphenol (5.4 g, 50 mmol, 1.25 equiv)and K₂CO₃ (8.28 g, 60 mmol, 1.5 equiv). The mixture was stirredovernight at room temp. The resulting mixture was treated with water(600 mL) to generate a precipitate. This mixture was stirred for 1 h,and the solids were separated and sequentially washed with a 1 N NaOHsolution (25 mL), water (25 mL) and pet ether (25 mL and pet ether (25mL) to give the desired product (7.05 g, 76%): mp 80-82° C.; TLC (30%EtOAc/70% pet ether) F_(ƒ)0.79; ¹H-NMR (DMSO-d₆) δ6 2.31 (s, 3H), 7.08(d, J=8.46 Hz, 2H), 7.19 (d, J=9.20 Hz, 1H), 7.24 (d, J=8.09 Hz, 2H),8.58 (dd, J=2.94, 8.82 Hz, 1H), 8.99 (d, J=2.95 Hz, 1H); FAB-MS m/z (relabundance) 231 ((M+H)⁺), 100%).

Step 2. 5-Amino-2-(4-methylphenoxy)pyridine Dihydrochloride

[0208] A solution 5-nitro-2-(4-methylphenoxy)pyridine (6.94 g, 30 mmol,1 eq) and EtOH (10 mL) in EtOAc (190 mL) was purged with argon thentreated with 10% Pd/C (0.60 g). The reaction mixture was then placedunder a H₂ atmosphere and was vigorously stirred for 2.5 h. The reactionmixture was filtered through a pad of Celite®. A solution of HCl in Et₂Owas added to the filtrate was added dropwise. The resulting precipitatewas separated and washed with EtOAc to give the desired product (7.56 g,92%): mp 208-210 ° C. (dec); TLC (50% EtOAc/50% pet ether) R_(ƒ)0.42;¹H-NMR (DMSO-d₆) δ2.25 (s, 3H), 6.98 (d, J=8.45 Hz, 2H), 7.04 (d, J=8.82Hz, 1H), 7.19 (d, J=8.09 Hz, 2H), 8.46 (dd, J=2.57, 8.46 Hz, 1), 8.63(d, J=2.57 Hz, 1H); EI-MS m/z (rel abundance) (M⁺, 100%).

A13i. General Method for Substituted Aniline Formation via NitroareneFormation Through Nucleophilic Aromatic Substitution, Followed byReduction

[0209]

Step 1. 4-(3-Thienylthio)-1-nitrobenzene

[0210] To a solution of 4-nitrothiophenol (80%pure; 1.2 g, 6.1 mmol),3-bromothiophene (1.0 g, 6.1 mmol) and copper(II) oxide (0.5 g, 3.7mmol) in anhydrous DMF (20 mL) was added KOH (0.3 g, 6.1 mmol), and theresulting mixture was heated at 130 ° C. with stirring for 42 h and thenallowed to cool to room temp. The reaction mixture was then poured intoa mixture of ice and a 6N HCl solution (200 mL) and the resultingaqueous mixture was extracted with EtOAc (3×100 mL). The combinedorganic layers were sequentially washed with a 1M NaOH solution (2×100mL) and a saturated NaCl solution (2×100 mL), dried (MgSO₄), andconcentrated in vacuo . The residual oil was purified by MPLC (silicagel; gradient from 10% EtOAc/90% hexane to 5% EtOAc/95% hexane) toafford of the desired product (0.5 g, 34%). GC-MS m/z 237 (M⁺).

Step 2. 4-(3-Thienylthio)aniline

[0211] 4-(3-Thienylthio)-1-nitrobenzene was reduced to the aniline in amanner analogous to that described in Method B 1.

A13j. General Method for Substituted Aniline Formation via NitroareneFormation Through Nucleophilic Aromatic Substitution, Followed byReduction

[0212]

4-(5-Pyrimininyloxy)aniline

[0213] 4-Aminophenol (1.0 g, 9.2 mmol) was dissolved in DMF (20 niL)then 5-bromopyrimidine (1.46 g, 9.2 mmol) and K₂CO₃ (1.9 g, 13.7 mmol)were added. The mixture was heated to 100 ° C. for 18 h and at 130 ° C.for 48 h at which GC-MS analysis indicated some remaining startingmaterial. The reaction mixture was cooled to room temp. and diluted withwater (50 mL). The resulting solution was extracted with EtOAc (100 mL).The organic layer was washed with a saturated NaCl solution (2×50 mL),dried (MgSO₄), and concentrated in vacuo. The residular solids werepurified by MPLC (50% EtOAc/50% hexanes) to give the desired amine(0.650 g, 38%).

A13k. General Method for Substituted Aniline Formation via NitroareneFormation Through Nucleophilic Aromatic Substitution, Followed byReduction

[0214]

Step 1. 5-Bromo-2-methoxypyridine

[0215] A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe(3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70 ° C. in a sealedreaction vessel for 42 h, then allowed to cool to room temp. Thereaction mixture was treated with water (50 mL) and extracted with EtOAc(2×100 mmL). The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure to give a pale yellow, volatile oil(4.1 g, 95% yield): TLC (10% EtOAc /90% hexane) R_(ƒ)0.57.

Step 2. 5-Hydroxy-2-methoxypyridine

[0216] To a stirred solution of 5-bromo-2-methoxypyridine (8.9 g, 47.9mmol) in THF (175 mL) at −78° C. was added an n-butyllithium solution(2.5 M in hexane; 28.7 mL, 71.8 mmol) dropwise and the resulting mixturewas allowed to stir at −78° C. for 45 min. Trimethyl borate (7.06 mL,62.2 mmol) was added via syringe and the resulting mixture was stirredfor an additional 2 h. The bright orange reaction mixture was warmed to0 ° C. and was treated with a mixture of a 3 N NaOH solution (25 mL,71.77 mmol) and a hydrogen peroxide solution (30%; approx. 50 mL). Theresulting yellow and slightly turbid reaction mixture was warmed to roomtemp. for 30 min and then heated to the reflux temp. for 1 h. Thereaction mixture was then allowed to cool to room temp. The aqueouslayer was neutralized with a 1 N HCl solution then extracted with Et₂O(2×100 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure to give a viscous yellow oil (3.5g,60%).

Step 3. 4-(5-(2-Methoxy)pyridyl)oxy-1-nitrobenzene

[0217] To a stirred slurry of NaH (97%, 1.0 g, 42 mmol) in anh DMF (100mL) was added a solution of 5-hydroxy-2-methoxypyridine (3.5g, 28 mmol)in DMF (100 mL). The resulting mixture was allowed to stir at room temp.for 1 h, 4-fluoronitrobenzene (3 mL, 28 mmol) was added via syringe. Thereaction mnixture was heated to 95 ° C. overnight, then treated withwater (25 mL) and extracted with EtOAc (2×75 mL). The organic layer wasdried (MgSO₄) and concentrated under reduced pressure. The residualbrown oil was crystalized EtOAc/hexane) to afford yellow crystals (5.23g, 75%).

Step 4. 4-(5-(2-Methoxy)pyridyl)oxyaniline

[0218] 4-(5 -(2-Methoxy)pyridyl)oxy-1-nitrobenzene was reduced to theaniline in a manner analogous to that described in Method B3d, Step2.

A14a. General Method for Substituted Aniline Synthesis via NucleophilicAromatic Substitution using a Halopyridine

[0219]

3-(4-Pyridinylthio)aniline

[0220] To a solution of 3-aminothiophenol (3.8 mL, 34 mmoles) in Am anhDMF (90mL) was added 4-chloropyridine hydrochloride (5.4 g, 35.6 mmoles)followed by K₂CO₃ (16.7 g, 121 mmoles). The reaction mixture was stirredat room temp. for 1.5 h, then diluted with EtOAc (100 mL) and water (100mL). The aqueous layer was back-extracted with EtOAc (2×100 mL). Thecombined organic layers were washed with a saturated NaCl solution (100mL), dried (MgSO₄), and concentrated under reduced pressure. The residuewas filtered through a pad of silica (gradient from 50% EtOAc/50% hexaneto 70% EtOAc/30% hexane) and the resulting material was triturated witha Et₂O/hexane solution to afford the desired product (4.6 g, 66%): TLC(100 % ethyl acetate) R_(ƒ)0.29; ¹H-NMR (DMSO-d₆ ) δ5.41 (s, 2H),6.64-6.74 (m, 3H), 7.01 (d, J=4.8, 2H), 7.14 (t, J=7.8 Hz, 1H), 8.32 (d,J=4.8, 2 ).

A14b. General Method for Substituted Aniline Synthesis via NucleophilicAromatic Substitution using a Ha;opyridine

[0221]

4-(2-Methyl-4-pyridinyloxy)aniline

[0222] To a solution of 4-aminophenol (3.6 g, 32.8 mmol) and4-chloropicoline (5.0 g, 39.3 mmol) in anh DMPU (50 mL) was addedpotassium tert-butoxide (7.4 g, 65.6 mmol) in one portion. The reactionmixture was heated at 100° C. with stirring for 18 h, then was allowedto cool to room temp. The resulting mixture was poured into water (200mL) and extracted with EtOAc (3×150 mL). The combined extracts weresequentially washed with water (3×100 niL) and a saturated NaCl solution(2×100 mL), dried (Na₂SO₄), and concentrated in vacuo. The resulting oilwas purified by flash chromatography (50 % EtOAc/50% hexane) to affordthe desired product as a yellow oil (0.7 g, 9%): Cl-MS m/z 201 ((M+H)⁺).

A14c. General Method for Substituted Aniline Synthesis via NucleophilicAromatic Substitution using a Halopyridine

[0223]

Step 1. Methyl(4-nitrophenyl)-4-pyridylamine

[0224] To a suspension of N-methyl-4-nitroaniline (2.0 g, 13.2 nmmol)and K₂CO₃ (7.2 g, 52.2 mmol) in DMPU (30mL) was added 4-chloropyridinehydrochloride (2.36 g, 15.77 mmol). The reaction mixture was heated at90° C. for 20 h, then cooled to room temperature. The resulting mixturewas diluted with water (100 mL) and extracted with EtOAc (100 mL). Theorganic layer was washed with water (100 mL), dried (Na₂SO4) andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, gradient from 80% EtOAc/20% hexanes to 100%EtOAc) to afford methyl(4-nitrophenyl)-4-pyridylamine (0.42 g)

Step 2. Methyl(4-aminophenyl)-4-pyridylamine

[0225] Methyl(4-nitrophenyl)-4-pyridylamine was reduced in a manneranalogous to that described in Method B 1.

A15. General Method of Substituted Aniline Synthesis via PhenolAlkylation Followed by Reduction of a Nitroarene

[0226]

Step 1. 4-(4-Butoxyphenyl)thio-1-nitrobenzene

[0227] To a solution of 4-(4-nitrophenyl-thio)phenol (1.50 g, 6.07 mmol)in anh DMF (75 ml) at 0° C. was added NaH (60% in mineral oil, 0.267 g,6.67 mmol). The brown suspension was stirred at 0 ° C. until gasevolution stopped (15 min), then a solution of iodobutane (1.12 g, 0.690ml, 6.07 mmol) in anh DMF (20 mL) was added dropwise over 15 min at 0°C. The reaction was stirred at room temp. for 18 h at which time TLCindicated the presence of unreacted phenol, and additional iodobutane(56 mg, 0.035 mL, 0.303 mmol, 0.05 equiv) and NaH (13 mg, 0.334 mmol)were added. The reaction was stirred an additional 6 h room temp., thenwas quenched by the addition of water (400 mL). The resulting mixturewas extracted with Et₂O (2×500 mL). The combibed organics were washedwith water (2×400 mL), dried (MgSO₄), and concentrated under reducedpressure to give a clear yellow oil, which was purified by silica gelchromatography (gradient from 20% EtOAc/80% hexane to 50% EtOAc/50%hexane) to give the product as a yellow solid (1.24 g, 67%): TLC (20%EtOAc/80% hexane) R_(ƒ)0.75; ¹H-NMR (DMSO-d₆) δ0.92 (t, J=7.5 Hz, 3 H),1.42 (app hex, J=7.5 Hz, 2H), 1.70 (m, 2H), 4.01 (t, J=6.6 Hz, 2H), 7.08(d, J=8.7 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 8.09(d, J=9 Hz, 2H).

Step 2. 4-(4-Butoxyphenyl)thioaniline4-(4-Butoxyphenyl)thio-1-nitrobenzene was reduced to the aniline in amanner analagous to that used in the preparation of3-(trifluoromethyl)-4-(4-pyridinylthio)aniline (Method B3b, Step 2): TLC(33% EtOAc/77% hexane) R_(ƒ)0.38. A16. General Method for Synthesis ofSubstituted Anilines by the Acylation of Diaminoarenes

[0228]

4-(4-tert-Butoxycarbamoylbenzyl)aniline

[0229] To a solution of 4,4′-methylenedianiline (3.00 g, 15.1 mmol) inanh THF (50 mmL) at room temp was added a solution of di-tert-butyldicarbonate (3.30 g, 15.1 mmol) in anh THF (10 mL). The reaction mixturewas heated at the reflux temp. for 3 h, at which time TLC indicated thepresence of unreacted methylenedianiline. Additional di-tert-butyldicarbonate (0.664 g, 3.03 mmol, 0.02 equiv) was added and the reactionstirred at the reflux temp. for 16 h. The resulting mixture was dilutedwith Et₂O (200 mL), sequentially washed with a saturated NaHCO₃ solution(100 ml), water (100 mL) and a saturated NaCl solution (50 mL), dried(MgSO₄), and concentrated under reduced pressure. The resulting whitesolid was purified by silica gel chromatography (gradient from 33%EtOAc/67% hexane to 50% EtOAc/50% hexane) to afford the desired productas a white solid ( 2.09 g, 46%): TLC (50% EtOAc/50% hexane) R_(ƒ)0.45;¹H-NMR (DMSO-d₆) δ1.43 (s, 9H), 3.63 (s, 2H), 4.85 (br s, 2H), 6.44 (d,J=8.4 Hz, 2H), 6.80 (d, J=8.1 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 7.28 (d,J=8.1 Hz, 2H), 9.18 (br s, 1H); FAB-MS m/z 298 (M⁺).

A17. General Method for the Synthesis of Aryl Amines via ElectrophilicNitration Followed by Reduction

[0230]

Step 1. 3-(4-Nitrobenzyl)pyridine

[0231] A solution of 3-benzylpyridine (4.0 g, 23.6 mmol) and 70% nitricacid (30 mL) was heated overnight at 50° C. The resulting mixture wasallowed to cool to room temp. then poured into ice water (350 mL). Theaqueous mixture then made basic with a 1N NaOH solution, then extractedwith Et₂O (4×100 mL). The combined extracts were sequentially washedwith water (3×100 mL) and a saturated NaCl solution (2×100 mL), dried(Na₂SO₄), and concentrated in vacuo. The residual oil was purified byMPLC (silica gel; 50 % EtOAc/50% hexane) then recrystallization(EtOAc/hexane) to afford the desired product (1.0 g, 22%): GC-MS m/z 214(M⁺).

Step 2. 3-(4-Pyridinyl)methylaniline

[0232] 3-(4-Nitrobenzyl)pyridine was reduced to the aniline in a manneranalogous to that described in Method B 1.

A18. General Method for Synthesis of Aryl Amines via Substitution withNitrobenzyl Halides Followed by Reduction

[0233]

Step 1. 4-(1-Imidazolylmethyl)-1-nitrobenzene

[0234] To a solution of imidazole (0.5 g, 7.3 mmol) and 4-nitrobenzylbromide (1.6 g, 7.3 mmol) in anh acetonitrile (30 mL) was added K₂CO₃(1.0 g, 7.3 mmol). The resulting mixture was stirred at rooom temp. for18 h and then poured into water (200 mL) and the resulting aqueoussolution wasextracted with EtOAc (3×50 mL). The combined organic layerswere sequentially washed with water (3×50 mL) and a saturated NaClsolution (2×50 mL), dried (MgSO₄), and concentrated in vacuo. Theresidual oil was purified by MPLC (silica gel; 25% EtOAc/75% hexane) toafford the desired product (1.0 g, 91%): El-MS m/z 203 (M⁺).

Step 2. 4-(1-Imidazolylmethyl)aniline

[0235] 4-(1Imidazolylmethyl)-1-nitrobenzene was reduced to the anilinein a manner analogous to that described in Method B2.

A19. Formation of Substituted Hydroxymethylanilines by Oxidation ofNitrobenzyl Compounds Followed by Reduction

[0236]

Step 1. 4-(1-Hydroxy-1-(4-pyridyl)methyl-1-nitrobenzene

[0237] To a stirred solution of 3-(4-nitrobenzyl)pyridine (6.0 g, 28mmol) in CH₂Cl₂ (90 mL) was added m-CPBA (5.80 g, 33.6 mmol) at 10° C.,and the mixture was stirred at room temp. overnight. The reactionmixture was successively washed with a 10% NaHSO₃ solution (50 mL), asaturated K₂CO₃ solution (50 mL) and a saturated NaCl solution (50 mL),dried (MgSO₄) and concentrated under reduced pressure. The resultingyellow solid (2.68 g) was dissolved in anh acetic anhydride (30 mL) andheated at the reflux temperature overnight. The mixture was concentratedunder reduced pressure. The residue was dissolved in MeOH (25 mL) andtreated with a 20% aqueous NH₃ solution (30 mL). The mixture was stirredat room temp. for 1 h, then was concentrated under reduced pressure. Theresidue was poured into a mixture of water (50 mL) and CH₂Cl₂ (50 mL).The organic layer was dried (MgSO₄), concentrated under reducedpressure, and purified by column chromatography (80% EtOAc/ 20% hexane)to afford the desired product as a white solid. (0.53 g, 8%): mp110-118° C.; TLC (80% EtOAc/20% hexane) R_(ƒ)0.12; FAB-MS m/z 367((M+H)⁺, 100%).

Step 2. 4-(1-Hydroxy-1-(4-pyridyl)methylaniline

[0238] 4-(1-Hydroxy-1-(4-pyridyl)-methyl-1-nitrobenzene was reduced tothe aniline in a manner analogous to that described in Method B3d,Step2.

A20. Formation of 2-(N-methylcarbamoyl)pyridines via the Meniscireaction

[0239]

Step 1. 2-(N-methylcarbamoyl)-4-chloropyridine.

[0240] (Caution: this is a highly hazardous, potentially explosivereaction.) To a solution of 4-chloropyridine (10.0 g) inN-methylformamide (250 mL) under argon at ambient temp was added conc.H₂SO₄ (3.55 mL) (exotherm). To this was added H₂O₂ (17 mL, 30% wt inH2O) followed by FeSO₄ 7H2O (0.55 g) to produce an exotherm. Thereaction was stirred in the dark at ambient temp for 1 h then was heatedslowly over 4 h at 45° C. When bubbling subsided,the reaction was heatedat 60° C. for 16 h. The opaque brown solution was diluted with H2O (700mL) fol.lowed by a 10% NaOH solution (250 mL). The aqueous mixture wasextracted with EtOAc (3×500 mL) and the organic layers were washedseparately with a saturated NaCl solution (3×150 mlL. The combinedorganics were dried (MgSO₄) and filtered through a pad of silica geleluting with EtOAc. The solvent was removed in vacuo and the brownresidue was purified by silica gel chromatography (gradient from 50%EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oilcrystallized at 0° C. over 72 h to give2-(N-methylcarbamoyl)-4-chloropyridine in yield (0.61 g, 5.3%): TLC (50%EtOAc/50% hexane) R_(ƒ)0.50; MS; ¹H NMR (CDCl₃): d 8.44 (d, 1 H, J=5.1Hz, CHN), 8.21 (s, 1H, CHCCO), 7.96 (b s, 1H, NH), 7.43 (dd, 1H, J=2.4,5.4 Hz, CICHCN), 3.04 (d, 3H, J=5.1 Hz, methyl); CI-MS m/z 171 ((M+H)⁺).

A21. Generalmethod for the Synthesis of ω-Sulfonylphenyl Anilines

[0241]

Step 1. 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene

[0242] To a solution of 4-(4-methylthiophenoxy)-1-nitrobenzene (2 g,7.66 mmol) in CH₂Cl₂ (75 mL) at 0° C. was slowly added mCPBA (57-86%, 4g), and the reaction mixture was stirred at room temperature for 5 h.The reaction mixture was treated with a 1 N NaOH solution (25 mL). Theorganic layer was sequentially washed with a 1N NaOH solution (25 mL),water (25 mL) and a saturated NaCl solution (25 mL), dried (MgSO₄), andconcentrated under reduced pressure to give4-(4-methylsulfonylphenoxy)-1-nitrobenzene as a solid (2.1 g).

Step 2. 4-(4-Methylsulfonylphenoxy)-1-aniline

[0243] 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene was reduced to theaniline in a manner anaologous to that described in Method B3d, step 2.

A22. General Method for Synthesis of ω-Alkoxy-ω-carboxyphenyl Anilines

[0244]

Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene

[0245] To a solution of -(3-carboxy-4-hydroxyphenoxy)-1-nitrobenzene(prepared in a manner analogous to that described in Method B3a, step 1,12 mmol) in acetone (50 mL) was added K₂CO₃ (5 g) and dimethyl sulfate(3.5 mL). The resulting mixture was heated aaaaaat the refluxtempoerature overnight, then cooled to room temperature and filteredthrough a pad of Celite®. The resulting solution was concentrrated underreduced pressure, absorbed onto silica gel, and purified by columnchromatography (50% EtOAc/50% hexane) to give4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a yellow powder(3 g): mp 115 118° C.

Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-1-nitrobenzene

[0246] A mixture of4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene (1.2 g), KOH (0.33g),and water (5 mL) in MeOH (45 mL) was stirred at room temperatureovernight and then heated at the reflux temperature for 4 h. Theresulting mixture was cooled to room temperature and concentrated underreduced pressure. The residue was dissolved in water (50 mL), and theaqueous mixture was made acidic with a 1N HCl solution. The resultingmixture was extracted with EtOAc (50 mL). The organic layer was dried(MgSO₄) and concentrated under reduced pressure to give4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (1.04 g).

B. General Methods of Urea Formation B1a. General Method for theReaction of an Aryl Amine with an Aryl Isocyanate

[0247]

N-(5-tert-Butyl-2-(3-tetrahydrofuranytoxy)phenyl)-N′(4-methylphenyl)urea

[0248] To a solution of 5-tert-butyl-2-(3-tetrahydrofuranyloxy)aniline(0.078 g, 0.33 mmol) in toluene (2.0 mL) was added p-tolyl isocyanate(0.048 g, 0.36 mmol) and the resulting mixture was allowed to stir atroom temp. for 8 h to produce a precipitate. The reaction mixture wasfiltered and the residue was sequentially washed with toluene andhexanes to give the desired urea as a white solid (0.091 g, 75%): mp229-231° C.; ¹H-NMR (DMSO-d₆) δ1.30 (s, 9H), 1.99-2.03 (m, 1H),2.19-2.23 (m, 4H), 3.69-3.76 (m, 1H), 3.86-3.93 (m, 3H), 4.98-5.01 (m,1H), 6.18-6.90 (m, 2H), 7.06 (d, J=8.09 Hz, 2H, 7.32 (d, J=8.09 Hz, 2H),7.84 (s, 1H), 8.22 (d, J=2.21 Hz, 1H), 9.26 (s, 1H).

B1b. General Method for the Reaction of an Aryl Amine with an ArylIsocyanate

[0249]

N-(2-Methoxy-5-(trifluoromethanesulfonyl)phenyl)-N′(4-methylphenyl)urea

[0250] p-Tolyl isocyanate (0.19 mL, 1.55 mmol) was added to a solutionof 2-methoxy-5-(trifluoromethanesulfonyl)aniline (0.330 g, 1.29 mmol) inEtOAc (5 mL), and the reaction mixture was stirred at room temp. for 18h. The resulting precipitate was collected by filtration and washed withEt₂O to give a white solid (0.28 g). This material was then purified byHPLC (C-18 column, 50% CH₃CN/50% H₂O ) and the resulting solids weretriturated with Et₂O to provide the title compound (0.198 g): ¹H-NMR(CDCl₃) δ7.08 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.8Hz, 1H), 7.71 (dd, J=2.6, 8.8 Hz, 1H), 8.66 (s, 1H), 8.90 (d, J=2.6 Hz,1H), 9.36 (s, 1H); FAB-MS m/s 389 ((M+1)⁺).

B1c. General Method for the Reaction of an Aryl Amine with an ArylIsocyanate

[0251]

N-(2-Methoxy-5-(difluoromethanesulfonyl)phenyl)-N′-(4-methylphenyl)urea

[0252] p-Tolyo isocyanate (0.058 mL, 0.46 mmol) was added to a solutionof 2-methoxy-5-(difluoromethanesulfonyl)aniline (0.100 g, 0.42 mmol) inEtOAc (0.5 mL) and the resulting mixture was stirred at room temp. for 3d. The resulting precipitate was filtered and washed with Et₂O toprovide the title compound as a white solid (0.092 g): ¹H-NMR (CDCl₃)δ2.22 (s, 3H) 4.01 (s, 3H), 7.02-7.36 (m, 6H), 7.54 (dd, J=2.4, 8.6 Hz,1H), 8.57 (s, 1H), 8.79 (d, J=2.6 Hz, 1H), 9.33 (s, 1H); EI-MS m/z 370(M⁺).

B1d. General Method for the Reaction of an Aryl Amine with an ArylIsocyanate

[0253]

N-(2,4-Dimethoxy-5-(trifluoromethyl)phenyl)-N′-(4-methylphenyl)urea

[0254] p-Tolyl isocyanate (0.16 mL, 1.24 mmol) was added to a solutionof 2,4-dimethoxy-5-(trifluoromethyl)aniline (0.25 g, 1.13 mmol) in EtOAc(3 mL) and the resulting mixture was stirred at room temp. for 18 h. Aresulting precipitate was washed with Et₂O to give the title compound asa white solid (0.36 g): ¹H-NMR (CDCl₃) δ2.21 (s, 3H). 3.97 (s, 3H), 3.86(s, 3H), 6.88 (s, 1H), 7.05 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H),8.13 (s, 1H), 8.33 (s, 1H), 9.09 (s, 1H); FAB-MS m/z 355 ((M+1)⁺).

B1e. General Method for the Reaction of an Aryl Amine with an ArylIsocyanate

[0255]

N-(3-Methoxy-2-naphthyl)-N′-(1-naphthyl)urea

[0256] To a solution of 2-amino-3-methoxynaphthalene (0.253 g, 1.50mmol) in CH₂Cl₂ (3 mL) at room temp. was added a solution of 1-naphthylisocyanate (0.247 g, 1.50 mmol) in CH₂Cl₂ (2 mL) and the resultingmixture was allowed to stir overnight. The resulting precipitate wasseparated and washed with CH₂Cl₂ to give the desired urea as a whitepowder (0.450 g, 90%): mp 235-236° C.; ¹H-NMR (DMSO-d₆) δ4.04 (s, 3H),7.28-7.32 (m, 2H), 7.38 (s, 1H) 7.44-7.72 (m, 6H), 7.90-7.93 (m, 1H),8.05-8.08 (m, 1H), 8.21-8.24 (m, 1H), 8.64 (s, 1H), 9.03 (s, 1H), 9.44(s, 1H); FAB-MS m/z 343 ((M+H)⁺).

B1f. General Method for the Reaction of an Aryl Amine with an ArylIsocyanate

[0257]

N-(5-tert-Butyl-2-(2-tert-butoxycarbonyloxy)ethoxy)phenyl)-N′-(4-methylphenyl)urea

[0258] A mixture of5-tert-butyl-2-(2-tert-butoxycarbonyloxy)ethoxy)aniline (Method A10,0.232 g, 0.75 mmol) and p-tolyl isocyanate (0.099 mL, 0.79 mmol) inEtOAc (1 mL) was stirred at room temp. for 3 d to produce a solid, whichwas separated. The filtrate was purified by column chromatography (100%CH₂Cl2) and the residue was triturated (Et₂O/hexane) to give the desiredproduct (0.262 g, 79%): mp 155-156 ° C.; TLC (20% EtOAc/80% hexane)F_(ƒ)0.49; ¹H-NMR (DMSO-d₆) δ1.22 (s, 9H), 1.37 (s, 9H), 2.21 (s, 3H),4.22-4.23 (m, 2H), 4.33-4.35 (m, 2H), 6.89-7.00 (m, 4H), 7.06 (d, J=8.5Hz, 2H) 7.32 (d, J=8.1 Hz, 2H), 7.96 (s, 1H); 8.22 (d, J=1.5 Hz, 1H),9.22 (s, 1H); FAB-MS m/z (rel abundance) 443 ((M+H)⁺, 6%).

B2a. General Method for Reaction of an Aryl Amine with Phosgene Followedby Addition of a Second Aryl Amine

[0259]

N-(2-Methoxy-5-(trifluoromethyl)phenyl)-N′-(3-(4-pyridinylthio)phenyl)urea

[0260] To a solution of pyridine (0.61 mL, 7.5 mmol, 3.0 equiv) andphosgene (20% in toluene; 2.65 mL, 5.0 mmol, 2.0 equiv) in CH₂Cl₂ (20rmL) was added 2-methoxy-5-(trifluoromethyl)aniline (0.48 g, 2.5 mmol)at 0° C. The resulting mixture was allowed warm to room temp. stirredfor 3 h, then treated with anh. toluene (100 mL) and concentrated underreduced pressure. The residue was suspended in a mixture of CH₂Cl₂ (10mL) and anh. pyridine (10 mL) and treated with3-(4-pyridinylthio)aniline (0.61 g, 2.5 mmol, 1.0 equiv). The mixturewas stirred overnight at room temp., then poured into water (50 mL) andextracted with CH₂Cl₂ (3×25 mL). The combined organic layers were dried(MgSO₄) and concentrated under reduced pressure. The residue wasdissolved in a minimal amount of CH₂Cl₂ and treated with pet. ether togive the desired product as a white precipitate (0.74 g, 70%): mp 202°C.; TLC (5% acetone/95% CH₂Cl₂) R_(ƒ)0.09; ¹H-NMR (DMSO-d₆) δ7.06 (d,J=5.5 Hz, 2H), 7.18 (dd, J=2.4, 4.6 Hz, 2H), 7.31 (dd, J=2.2, 9.2 Hz,1H), 7.44 (d, J=5.7 Hz, 1H), 7.45 (s, 1H), 7.79 (d, J=2.2 Hz, 1H), 8.37(s, 2H), 8.50 (dd, J=2.2, 9.2 Hz, 2H), 9.63 (s, 1H), 9.84 (s, 1H);FAB-MS m/z 420 ((M+H)⁺,

B2b. General Method for Reaction of an Aryl Amine with Phosgene Followedby Addition of a Second Aryl Amine

[0261]

N-(2-Methoxy-5-(trifluoromethyl)phenyl)-N′(4-(4-pyridinylthio)phenyl)urea

[0262] To a solution of pyridine (0.61 mL, 7.5 mmol, 3.0 equiv) andphosgene (20% in toluene; 2.65 mL, 5.0 mmol, 2.0 equiv) in CH₂Cl₂ (20mL) was added 4-(4-pyridinylthio)aniline (0.506 g, 2.5 mmol) at 0° C.After stirring for 3 h at room temp., the mixture was treated with anh.toluene (100 mL) then concentrated under reduced pressure. The residuewas suspended in a mixture of CH₂Cl₂ (10 mL) and anh. pyridine (10 mL)and treated with 2-methoxy-5-(trifluoromethyl)aniline (0.50 g, 2.5 mmol,1.0 equiv). After stirring the mixture overnight at room temp., it waspoured into a 1 N NaOH solution (50 mL) and extracted with CH₂Cl₂ (3×25mL). The combined organic layers were dried (MgSO₄) and concentratedunder reduced pressure to give the desired urea (0.74 g, 71%): mp 215°C.; TLC (5% acetone/95% CH₂Cl₂) R_(ƒ)0.08; ¹H-NMR (DMSO-d₆) δ3.96 (s,3H), 6.94 (dd, J=1.1, 4.8 Hz, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.32 (dd,J=2.2, 9.3 Hz, 1H), 7.50 (d J=8.8 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 8.32(d, J=5.1 Hz, 2H), 8.53 (d, J=0.7 Hz, 1H), 8.58 (s, 1H), 9.70 (s, 1H);FAB-MS m/z 420 ((M+H)⁺).

B3a. General Method for the Reaction of an Aryl Amine with Phosgene withIsolation of the Isocyanate, Followed by Reaction with a Second ArylAmine

[0263]

Step 1. 5-(Difluoromethanesulfonyl)-2-methoxyphenyl isocyanate

[0264] To a solution of phosgene (1.95 M in toluene; 3.0 mL, 5.9 mmol)in CH₂Cl₂ (40 mL) at 0° C. was added a solution of5-(difluoromethanesulfonyl)-2-methoxyaniline (0.70 g, 2.95 mmol) andpyridine (0.44 mL, 8.85 mmol) in CH₂Cl₂ (10 mL) dropwise. After beingstirred at 0° C. for 30 min and at room temp. for 3 h, the reactionmixture was concentrated under reduced pressure, then treated withtoluene (50 mL). The resulting mixture was concentrated under reducedpressure, then was treated with Et₂O (50 mL) to produce a precipitate(pyridinium hydrochloride). The resulting filtrate was concentratedunder reduced pressure to provide the title compound as a white solid(0.33 g). This material was used in the next step without furtherpurification.

Step 2.N-(2-Methoxy-5-(difluoromethanesulfonyl)phenyl)-N′-(2-fluoro-4-methylphenyl)urea

[0265] 2-Fluoro-4-methylaniline (0.022 mL, 0.19 mmol) was added to asolution of 5-(difluoromethanesulfonyl)-2-methoxyphenyl isocyanate(0.046 g, 0.17 mmol) in EtOAc (1 mL). The reaction mixture was stirredat room temp. for 3 d. The resulting precipitate was washed with Et₂O toprovide the title compound as a white solid (0.055 g): ¹H-NMR (CDCl₃)δ2.24 (s, 3H), 4.01 (s, 3H), 6.93 (d, J=8.5 Hz, 1H), 7.01-7.36 (m, 3H),7.56 (dd, J=2.4, 8.6 Hz, 1H), 7.98 (app t, J=8.6 Hz, 1H), 8.79 (d, J=2.2Hz, 1H), 9.07 (s, 1H), 9.26 (s, 1H); FAB-MS m/z 389 ((M+l)⁺).

B3b. General Method for the Reaction of an Aryl Amine with Phosgene withIsolation of the Isocyanate, Followed by Reaction with a Second ArylAmine

[0266]

Step 1. 2-Methoxy-5-trifluoromethylphenyl Isocyanate

[0267] To a solution of phosgene (1.93 M in toluene; 16 mL, 31.4 mmol)in CH₂Cl₂ (120 mL) at 0° C. was added a solution of2-methoxy-5-(trifluoromethyl)aniline (3.0 g, 15.7 mmol) and pyridine(2.3 mL, 47.1 mmol) in CH₂Cl₂ (30 mL) dropwise. The resulting mixturewas stirred at 0° C. for 30 min and at room temp for 3 h, thenconcentrated under reduced pressure. The residue was diluted withtoluene (30 mL), concentrated under reduced pressure, and treated withEt₂O. The resulting precipitate (pyridinium hydrochloride) was removedand the filtrate was concentrated under redeuced pressure to give thetitle compound as a yellow oil (3.0 g) which crystallized upon standingat room temp. for a few days.

Step 2. N-(2-Methoxy-5-(trifluoromethyl)phenyl)- N′-(4-fluorophenyl)urea

[0268] 4-Fluoroaniline (0.24 mL, 2.53 mmol) was added to a solution of2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.50 g, 2.30 mmol) inEtOAc (6 mL) and the reaction mixture was stirred at room temp. for 3 d.The resulting precipitate was washed with Et₂O to give the titlecompound as a white solid (0.60 g): NMR: 3.94 (s, 3H). 7.13-7.18 (m,3H), 7.30 (dd, J=1.5, 8.4 Hz, 1H), 7.44 (m, 2H), 8.45 (s, 1H), 8.52 (d,J=2.2 Hz, 1H), 9.42 (s, 1H); FAB-MS m/z 329 ((M+1)⁺).

B4. General Method for Urea Formation via Curtius Rearrangement,Followed by Trapping with an Amine

[0269]

N-(3-Methoxy-2-naphthyl)-N′-(4-methylphenyl)urea

[0270] To a solution of 3-methoxy-2-naphthoic acid (Method A6, Step 2;0.762 g, 3.80 mmol) and Et₃N (0.588 mL, 4.2 mmol) in anh toluene (20 mL)at room temp. was added a solution of diphenylphosphoryl azide (1.16 g,4.2 mmol) in toluene (5 mL). The resulting mixture was heated to 80° C.for 2 h, cooled to room temp., and p-toluidine (0.455 g, 4.1 mmol) wasadded. The mixture was heated at 80° C. overnight, cooled to room temp.,quenched with a 10% citric acid solution, and extracted with EtOAc (2×25mL). The combined organic layers were washed with a saturated NaClsolution (25 miL), dried (MgSO₄), and concentrated in vacuo. The residuewas triturated with CH₂Cl₂ to give the desired urea as white powder(0.700 g, 61%): mp 171-172° C.; ¹H-NMR (DMSO-d₆) δ2.22 (s, 3H), 3.99 (s,3H), 7.07 (d, J=8.49 Hz, 2H), 7.27-7.36 (m, 5H), 7.67-7.72 (m, 2H), 8.43(s, 1H), 8.57 (s, 1H), 9.33 (s, 1H); FAB-MS m/z 307 ((M+H)⁺).

B5. General Method for the Reaction of Substituted Aniline withN,N′-Carbonyldiimidazole Followed by Reaction with a Second Amine

[0271]

N-(5-Chloro-2-hydroxy4-nitrophenyl)-N′-(4-(4-pyridinylmethyl)phenyl)urea

[0272] A solution of 4-(4-pyridinylmethyl)aniline (0.300 g, 1.63 mmol)and N,N′-carbonyldiimidazole (0.268 g, 1.65 mmol) in CH₂Cl₂ (10 mL) wasstirred at room temp. for 1 h at which time TLC analysis indicated nostarting aniline. The reaction mixture was then treated with2-amino-4-chloro-5-nitrophenol (0.318 g, 1.65 mmol) and stirred at40-45° C. for 48 h. The resulting mixture was cooled to room temp. anddiluted with EtOAc (25 mL). The resulting precipitate was separated togive the desired product (0.416 g, 64%): TLC (50% acetone/50% CH₂Cl₂)R_(ƒ)0.40; ¹H-NMR (DMSO-d₆) δ3.90 (s, 2H), 7.18 (d, J=8.4 Hz, 2H),7.21(d, J=6 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), (s, 1H), 8.43-8.45 (m, 3H),8.78 (s, 1H), 9.56 (s, 1H), 11.8 (br s, 1H); FAB-MS m/z (rel abundance)399 ((M+H)⁺, 10%).

B6. General Method for the Synthesis of Symmetrical Diphenyl Ureas asSide-Products of Urea Forming reactions

[0273]

Bis(4-chloro-3-(trifluoromethyl)phenyl)urea

[0274] To a solution of 5-amino-3-tert-butylisoxazole (0.100 g) in anhtoluene (5 niL) was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate(0.395 g). The reaction vessel was sealed, heated at 85° C. for 24 h,and cooled to room temp. The reaction mixture was added to a slurry ofDowex®50WX2-100 resin (0.5 g) in CH₂Cl₂ (40 mL), and the resultingmixture was stirred vigorously for 72 h. The mixture was filtered andthe filtrate was concentrated under reduced pressure. The residue waspurified by column chromatography (gradient form 100% CH₂Cl₂ to 5%MeOH/95% CH₂Cl₂) to give bis(4-chloro-3-(trifluoromethyl)phenyl)ureafollowed byN-(3-tert-butyl-5-isoxazolyl)-N′-(4-chloro-3-(trifuoromethyl)phenyl)urea.The residue from the symmetrical urea fractions was triturated(Et₂O/hexane) to give the urea as a white solid (0.110 g): TLC (3%MeOH/97% CH₂Cl₂) R_(ƒ)0.55; FAB-MS m/z 417 ((M+H)⁺).

C. Urea Interconversions and Misc. Reactions C1. General Method forAlkylation of Hydroxyphenyl Ureas

[0275]

Step 1.N-(2-Hydroxy-5-(trifluoromethylthio)phenyl)-N′-(4-methylphenyl)urea

[0276] p-Tolyl Tolyl isocyanate (0.066 mL, 0.52 mmol) was added to asolution of 2-hydroxy-5-(trifluoromethylthio)aniline (0.100 g, 0.48mmol) in EtOAc (2 mL) and the reaction mixture was stirred at room temp.for 2 d. The resulting precipitate was washed with EtOAc to provide thetitle compound (0.13 g): ¹H-NMR (CDCl₃) δ2.24 (s, 3H). 7.44-7.03 (m,6H), 8.46 (s, 1H), 8.60 (d, J=1.8 Hz, 1H), 9.16 (s, 1H), 10.41 (s, 1H);FAB-MS m/z 343 ((M+1)⁺). This material was used in the next step withoutpurification.

Step 2.N-(2-Methoxy-5-(trifluoromethylthio)phenyl)-N′-(4-methylphenyl)urea

[0277] A solution ofN-(2-hydroxy-5-(trifluoromethylthio)phenyl)-N′-(4-methylphenyl)urea(0.125 g, 0.36 mmol), iodomethane (0.045 mL, 0.73 mmol), and K₂CO₃ (100mg, 0.73 mmol) in acetone (2 mL) was heated at the reflux temp. for 6 h,then was cooled to room temp. and concentrated under reduced pressure.The residue was dissolved in a minimal amount of MeOH, absorbed ontosilica gel, and then purified by flash chromatograpy (3% Et₂O/0/97%CH₂Cl₂) to provide the title compound as a white solid (68 mg): ¹H-NMR(CDCl₃) δ2.22 (s, 3H), 3.92 (s, 3H), 7.05-7.32 (m, 6H), 8.37 (s, 1H),8.52 (d, J=2.2 Hz, 1H), 9.27 (s, 1H); FAB-MS m/z 357 ((M+1)⁺).

C2. General Method for the Reduction of Nitro-Containing Ureas

[0278]

N-(5-tert-Butyl-2-methoxyphenyl)-N′-(2-amino-4-methylphenyl)urea

[0279] A solution ofN-(5-tert-butyl-2-methoxyphenyl)-N′-(2-nitro-4-methylphenyl)urea(prepared in a manner analogous to Method B1a; 4.0 g, 11.2 mmol) in EtOH(100 mL) was added to a slurry of 10% Pd/C (0.40 g) in EtOH (10 mL), andthe resulting mixture was stirred under an atmosphere of H₂ (balloon) atroom temp. for 18 h. The mixture was filtered through a pad of Celite®and concentrated in vacuo to afford the desired product (3.42 g, 94%) asa powder: mp 165-166° C.; ¹H-NMR (DMSO-d₆) δ1.30 (s, 9H), 2.26 (s, 3H),3.50 (br s, 2H), 3.71 (s, 3H), 6.39 (br s, 1H), 6.62 (s, 1H), 6.73 (d,J=8.46 Hz, 1H), 6.99 (dd, J=2.21, 8.46 Hz, 1H), 7.05 (d, J=8.46 Hz, 1H),7.29 (s, 1H), 8.22 (d, J=2.57 Hz, 1H); FAB-MS m/z 328 ((M+H)⁺).

C3. General Method of Thiourea Formation by Reaction with aThioisocyanate

[0280]

N-(5-tert-Butyl-2-methoxyphenyl)-N′-(1-naphthyl)thiourea

[0281] To a solution of 5-tert-butyl-2-methoxyaniline (0.372 g, 2.07mmol) in toluene (5 mL) was added 1-naphthyl thioisocyanate (0.384 g,2.07 mmol) and the resulting mixture was allowed to stir at room temp.for 8 h to produce a precipitate. The solids were separated andsequentially washed with toluene and hexane to give the desired productas an off-white pwoder (0.364 g, 48%): mp 158-160° C.; ¹H-NMR (DMSO-d₆)δ1.31 (s, 9H), 3.59 (s, 3H), 6.74 (d, J=8.46 Hz, 1H), 7.13 (dd, J=2.21,8.46 Hz, 1H), 7.53-7.62 (m, 4H), 7.88-7.95 (m, 4H), 8.06-8.08 (m, 1H),8.09 (br s, 1H); FAB-MS m/z 365 ((M+H)⁺).

C4. General Method for Deprotection of tert-Butyl Carbonate-ContainingUreas

[0282]

N-(5-tert-Butyl-2-(2-hydroxyethoxy)phenyl)-N′-(4-methylphenyl)urea

[0283] A solution ofN-(5-tert-butyl-2-(2-tert-butoxycarbonyloxy)ethoxy)phenyl)-N′-(4-methylphenyl)urea(Method B1f; 0.237 g, 0.54 mmol) and TFA (0.21 mL, 2.7 mmol) in CH₂Cl₂(2 mL) was stirred at room temp for 18 h, then was washed with asaturated NaHCO₃ solution (2 mL). The organic layer was dried by passingthrough 1PS filter paper (Whatman®) and concentrated under reducedpressure. The resulting white foam was triturated (Et₂O/hexane), thenrecrystallized (Et₂O) to give the desired product (3.7 mg): TLC (50%EtOAc/50% hexane) R_(ƒ)0.62; ¹H-NMR (DMSO-d₆) δ1.22 (s, 9H), 3.75-3.76(m, 2H), 4.00-4.03 (m, 2H), 4.80 (t, J=5.0 Hz, 1H), 6.88-6.89 (m, 4H),7.06 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 7.97 (s, 1H), 8.20 br s,1H), 9.14 (s, 1H); FAB-MS m/z (rel abundance) 343 ((M+H)⁺, 100%).

[0284] The following compounds have been synthesized according to theGeneral Methods listed above: TABLE 1 2-Substituted-5-tert-butylphenylUreas

mp TLC Solvent Mass Synth. Example R¹ R² (° C.) R_(f) System Spec.Source Method 1 OH

0.54 2% MeOH/98% CH2Cl2 299 (M + H)+ FAB B1d 2 OMe

199-200 313 (M + H)+ FAB B1d 3 OMe

208-209 390 (M+) EI B1d 4 OMe

192-194 389 (M + H)+ FAB B1d 5 OMe

0.58 50% EtOAc/50% hexane 347 (M + H)+ FAB B3b 6 OMe

0.62 50% EtOAc/50% hexane 351 (M + H)+ FAB B3b 7 OMe

0.71 50% EtOAc/50% hexane 331 (M + H)+ FAB B1d 8 OMe

0.74 50% EtOAc/50% hexane 331 (M + H)+ FAB B3b 9 OMe

0.66 20% EtOAc/80% hexane 327 (M + H)+ FAB B1d 10 OMe

0.62 20% EtOAc/80% hexane 331 (M + H)+ FAB B1d 11 OMe

0.42 13% EtOAc/87% hexane 335 (M + H)+ FAB B1d 12 OMe

0.52 2% MeOH/98% CH2Cl2 327 (M + H)+ FAB B1d 13 OMe

0.56 2% MeOH/98% CH2Cl2 335 (M + H)+ FAB B1d 14 OMe

0.48 2% MeOH/98% CH2Cl2 351 (M + H)+ FAB B1d 15 OMe

0.50 2% MeOH/98% CH2Cl2 347 (M + H)+ FAB B1d 16 OMe

201-202 390 (M + H)+ FAB B2a 17 OMe

199-200 390 (M + H)+ FAB B2a 18 OMe

198-199 0.45 25% EtOAc/75% hexane B1a 19 OMe

181-182 389 (M + H)+ CI B2a 20 OMe

181-183 390 (M+) EI B1a 21 OMe

175-177 358 (M + H)+ FAB B1a 22 OMe

219-220 358 (M + H)+ FAB B1a 23 OMe

165-166 328 (M + H)+ FAB C2 24 OMe

102-104 271 (M + H)+ FAB C2 25 OMe

236-238 349 (M + H)+ FAB B1a 26 OMe

192-194 367 (M + H)+ FAB B1a 27 OMe

137-140 550 (M + H)+ FAB B2a 28 OMe

197-199 434 (M + H)+ CI A8, B2a 29 OMe

212-215 416 (M + H)+ FAB B2a 30 OMe

195 405 (M + H)+ FAB B1e 31 OMe

110 0.07 5% acetone/95% CH2Cl2 408 (M + H)+ FAB B2b 32 OMe

185 0.67 5% acetone/95% CH2Cl2 425 (M + H)+ FAB B2a 33 OMe

214-215 0.54 5% acetone/95% CH2Cl2 448 (M + H)+ FAB B2a 34 OMe

180 0.56 5% acetone/95% CH2Cl2 421 (M + H)+ FAB B2a 35

0.67 50% EtOAc/50% hexane 343 (M + H)+ FAB A10, B1f, C4 36

0.45 50% EtOAc/50% hexane 340 (M + H)+ FAB B1d 37

222-223 354 (M + H)+ ES B1c 38

203-205 366 (M + H)+ FAB B1d 39

230-232 367 (M + H)+ FAB B1d 40

197-198 406 (M + H)+ FAB A9, B1a 41

204-205 392 (M + H)+ FAB A9, B1a 42

217-218 424 (M + H)+ FAB A9, B1a 43

187-188 370 (M + H)+ FAB A9, B1a 44

118-120 462 (M + H)+ FAB A9, B1a 45

146-148 448 (M + H)+ FAB A9, B1a 46

110-113 480 (M + H)+ FAB A9, B1a 47

95-100 400 (M + H)+ FAB A9, B1a 48

107-110 398 (M + H)+ FAB A9, B1a 49

180-182 472 (M + H)+ FAB A9, B1a 50

217-219 388 (M + H)+ FAB A9, R1a 51

116-120 420 (M + H)+ FAB A9, B1a 52

100-105 406 (M + H)+ FAB A9, B1a 53

103-105 438 (M + H)+ FAB A9, B1a 54

118-120 384 (M + H)+ FAB A9, B1a 55

125-128 394 (M + H)+ FAB A1, B1a 56

227-230 468 (M + H)+ FAB A1, B1a 57

154-156 434 (M + H)+ FAB A1, B1a 58

169-171 373 (M + H)+ FAB A2, B1a 59

157-159 423 (M + H)+ FAB A2, B1a 60

229-231 369 (M + H)+ FAB A2, B1a 61

200-204 468 (M + H)+ FAB B2a 62

187-188 508 (M + H)+ FAB B2a 63

204-206 413 (M + H)+ FAB B1a 64

192-194 389 (M + H)+ FAB A7, B1a 65

183-185 425 (M + H)+ FAB A7, B1a 66

159-160 443 (M + H)+ FAB A7, B1a 67

179-180 411 (M + H)+ FAB A7, B1a 68

0.06 10% EtOAc/90% hexane 408 (M + H)+ FAB A7, B1a 69

227-229 377 (M + H)+ FAB A7, B1a 70

216-217 381 (M + H)+ FAB A7, B1a 71

213-214 431 (M + H)+ FAB A7, B1a 72

200-201 399 (M + H)+ FAB A7, B1a 73

134-136 443 (M+) EI A7, B1a 74

185-186 459 (M + H)+ FAB A7, B1a 75

207-208 419 (M + H)+ FAB A7, B1a

[0285] TABLE 2 2-Substituted-5-(trifluoromethyl)phenyl Ureas

mp TLC Solvent Mass Synth. Example R¹ R² (° C.) R_(f) System Spec.Source Method 76 OMe

185-186 325 (M + H)+ FAB B1d 77 OMe

0.22 20% EtOAc/80% hexane 329 (M + H)+ FAB B3b 78 OMe

0.49 20% EtOAc/80% hexane 343 (M + H)+ FAB B3b 79 OMe

0.32 20% EtOAc/80% hexane 343 (M + H)+ FAB B3b 80 OMe

0.37 20% EtOAc/80% hexane 359 (M + H)+ FAB B3b 81 OMe

0.44 20% EtOAc/80% hexane 363 (M + H)+ FAB B3b 82 OMe

0.68 50% EtOAc/50% hexane 339 (M + H)+ FAB B1d 83 OMe

0.68 50% EtOAc/50% hexane 343 (M + H)+ FAB B1d 84 OMe

0.60 50% EtOAc/50% hexane 347 (M + H)+ FAB B1d 85 OMe

0.53 2% MeOH/98% CH2Cl2 339 (M + H)+ FAB B1d 86 OMe

0.29 2% MeOH/98% CH2Cl2 347 (M + H)+ FAB B1d 87 OMe

0.27 2% MeOH/98% CH2Cl2 363 (M + H)+ FAB B1d 88 OMe

0.45 2% MeOH/98% CH2Cl2 359 (M + H)+ FAB B1d 89 OMe

184-185 401 (M + H)+ FAB B2a 90 OMe

176-178 402 (M+) EI B1a 91 OMe

231-233 361 (M + H)+ FAB B1a 92 OMe

192-194 379 (M + H)+ FAB B1a 93 OMe

198 417 (M + H)+ FAB B1e 94 OMe

206 0.58 5% acetone/95% CH2Cl2 437 (M + H)+ FAB B2a 95 OMe

98-99 0.50 5% acetone/95% CH2Cl2 B2a 96 OMe

190 0.65 5% acetone/95% CH2Cl2 B2a 97 OMe

194 0.76 5% acetone/95% CH2Cl2 464 (M + H)+ FAB B2a 98 OMe

210-211 0.07 5% acetone/95% CH2Cl2 402 (M + H)+ FAB B2a 99 OMe

202 0.09 5% acetone/95% CH2Cl2 420 (M + H)+ FAB B2a 100 OMe

215 0.08 5% acetone/95% CH2Cl2 420 (M + H)+ FAB B2a 101 OMe

206 0.05 5% acetone/95% CH2Cl2 404 (M + H)+ FAB B2a 102 OMe

0.78 5% acetone/95% CH2Cl2 471 (M + H)+ FAB B1a 103 OMe

471 (M + H)+ FAB B1a 104 OMe

487 (M + H)+ FAB B1a 105

0.65 20% EtOAc/80% hexane 352 (M + H)+ FAB B1d 106

159-160 0.33 25% EtOAc/75% hexane 353 (M + H)+ FAB A5, B1a 107

152-153 0.35 25% EtOAc/75% hexane 339 (M + H)+ FAB A5, B1a 108 SMe

246-247 0.30 25% EtOAc/75% hexane 377 (M + H)+ FAB B1a 109 SMe

210-211 0.35 25% EtOAc/75% hexane 345 (M + H)+ CI B1a 110 SMe

195-196 0.35 25% EtOAc/75% hexane 314 (M + H)+ FAB B1a 111 SMe

196-197 0.40 25% EtOAc/75% hexane 395 (M + H)+ FAB B1a

[0286] TABLE 3 S-Substituted 2-Methoxy-5-sulfonylphenyl Ureas

mp TLC Solvent Mass Synth. Example R² R³ (° C.) R_(f) System Spec.Source Method 112

F 205-207 339 (M + H)+ HPLC ES-MS B1d 113

CHF₂ 195-196 370 (M+) EI B1d 114

CHF₂ 0.46 50% EtOAc/50% hexane 389 (M + H)+ FAB B3a 115

CHF₂ 0.21 50% EtOAc/50% hexane 405 (M + H)+ FAB B3a 116

CHF₂ 0.23 20% EtOAc/80% hexane 409 (M + H)+ FAB B3a 117

CHF₂ 0.40 50% EtOAc/50% hexane 389 (M + H)+ FAB B3a 118

CHF₂ 0.53 50% EtOAc/50% hexane 375 (M + H)+ FAB B3a 119

CHF₂ 0.58 50% EtOAc/50% hexane 389 (M + H)+ FAB B1c 120

CHF₂ 0.48 50% EtOAc/50% hexane 389 (M + H)+ FAB B1d 121

CHF₂ 0.44 50% EtOAc/50% hexane 393 (M + H)+ FAB B1c 122

CHF₂ 0.33 5% MeOH/95% CH2Cl2 385 (M + H)+ FAB B1c 123

CHF₂ 393 (M + H)+ FAB B1c 124

CHF₂ 409 (M + H)+ FAB B1c 125

CHF₂ 405 (M + H)+ FAB B1c 126

CHF₂ 0.56 50% EtOAc/50% hexane 385 (M + H)+ FAB B1c 127

CF₃ 0.56 50% EtOAc/50% hexane 389 (M + H)+ FAB A3, B1d

[0287] TABLE 4 3-Substituted-2-naphthyl Ureas

mp TLC Solvent Mass Synth. Example R¹ R² (° C.) R_(f) System Spec.Source Method 128 OMe

171-172 0.40 25% EtOAc/75% hexane 307 (M + H)+ FAB B4 129 OMe

197-199 0.40 14% EtOAc/86% hexane 325 (M + H)+ FAB B4 130 OMe

235-236 0.45 25% EtOAc/75% hexane 343 (M + H)+ FAB A6, B1a 131 OMe

236-237 0.45 25% EtOAc/75% hexane 311 (M + H)+ FAB A6, B1a 132 OMe

209-211 311 (M + H)+ FAB A6, B1a 133 OMe

225-226 321 (M + H)+ FAB A6, B1a 134 OMe

199-200 395 (M + H)+ FAB A6, B1a 135 OMe

227-228 361 (M + H)+ FAB A6, B1a 136 OMe

207-208 327 (M + H)+ FAB A6, B1a 137 OMe

234-235 361 (M + H)+ FAB A6, B1a 138 OMe

228-229 352 (M + H)+ FAB A6, B1a 139 OMe

190-195 323 (M + H)+ FAB A6, B1a 140 OMe

203-205 310 (M + H)+ FAB A6, B1a 141 OMe

209-210 307 (M + H)+ FAB A6, B1a 142 OMe

200-201 323 (M + H)+ FAB A6, B1a 143 OMe

201-202 307 (M + H)+ FAB A6, B1a 144 OMe

216-218 385 (M + H)+ FAB A6, B1a 145 OMe

181-182 361 (M + H)+ FAB A6, B1a 146 OMe

238-239 0.25 25% EtOAc/75% hexane 402 (M + H)+ FAB B4 147 OMe

199-200 0.20 25% EtOAc/75% hexane 384 (M + H)+ FAB B4 148 OMe

175-176 321 (M + H)+ FAB A6, B1a 149 OMe

164-166 544 (M + H)+ FAB A6, B1a 150 OMe

206-209 446 (M + H)+ FAB A6, B1a 151 OMe

234-237 410 (M + H)+ FAB B2a 152 OMe

209-211 0.40 25% EtOAc/75% hexane 414 (M+) EI B4

[0288] TABLE 5 Misc. Ureas mp TLC Solvent Mass Synth. Example R² (° C.)R_(f) System Spec. Source Method 153

183-184 327 (M + H)+ FAB B1d 154

156-157 312 (M+) EI B1d 155

0.46 50% EtOAc/50% hexane 291 (M + H)+ FAB B1d 156

157

0.40 50% acetone/50% CH2Cl2 399 (M + H)+ FAB B5 158

219-221 336 (M + H)+ FAB B1d 159

204-205 305 (M + H)+ FAB B1d 160

208-210 302 (M + H)+ FAB B1d 161

226-228 355 (M + H)+ FAB B1d 162

160-162 328 (M + H)+ FAB B1a 163

0.85 50% EtOAc/50% hexane 291 (M + H)+ FAB B1b 164

225-226 0.60 25% EtOAc/75% hexane 367 (M + H)+ FAB A4, B1a 165

0.55 3% MeOH/97% CH2Cl2 417 (M + H)+ FAB B6 166

169-171 407 (M + H)+ FAB B1a 167

158-160 C3 365 (M + H)+ FAB C3

BIOLOGICAL EXAMPLES b 38 Kinase Assay

[0289] The in vitro inhibitory properties of compounds were determinedusing a p38 kinase inhibition assay. P38 activity was detected using anin vitro kinase assay run in 96-well microtiter plates. Recombinanthuman p38 (0.5 μg/mL) was mixed with substrate (myelin basic protein, 5μg/mL) in kinase buffer (25 mM Hepes, 20 mM MgCl₂ and 150 mM NaCl) andcompound. One μgCi/well of ³³P-labeled ATP (10 μM) was added to a finalvolume of 100 μL. The reaction was run at 32 ° C. for 30 min. andstopped with a 1M HCl solution. The amount of radioactivity incorporatedinto the substrate was determined by trapping the labeled substrate ontonegatively charged glass fiber filter paper using a 1% phosphoric acidsolution and read with a scintillation counter. Negative controlsinclude substrate plus ATP alone.

[0290] All compounds exemplified displayed p38 IC₅₀ s of between 1 nMand 10 μM.

LPS Induced TNFα Production in Mice

[0291] The in vivo inhibitory properties of selected compounds weredetermined using a murine LPS induced TNFα production in vivo model.BALB/c mice (Charles River Breeding Laboratories; Kingston, N.Y.) ingroups of ten were treated with either vehicle or compound by the routenoted. After one hour, endotoxin (E. coli lipopolysaccharide (LPS) 100μg) was administered intraperitoneally (i.p.). After 90 min, animalswere euthanized by carbon dioxide asphyxiation and plasma was obtainedfrom individual animals by cardiac puncture ionto heparinized tubes. Thesamples were clarified by centrifugation at 12,500×g for 5 min at 4 ° C.The supernatants were decanted to new tubes, which were stored as neededat −20 ° C. TNFU. levels in sera were measured using a commercial murineTNF ELISA kit (Genzyme).

[0292] The preceeding examples can be repeated with similar success bysubstituting the generically of specifically described reactants and/oroperating conditions of this invention for those used in the preceedingexamples

[0293] From the foregoing discussion, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A method of treating a disease, other thancancer, mediated by p-38, comprising administering a compound of formulaI

B is a substituted or unsubstituted, up to tricyclic aryl or heteroarylmoiety of up to 30 carbon atoms with at least one 6-member aromaticstructure containing 0-4 members of the group consisting of nitrogen,oxygen and sulfur, wherein if B is substituted, it is substituted by oneor more substituents selected from the group consisting of halogen, upto per-halo, and W_(n), wherein n is 0-3 and each W is independentlyselected from the group consisting of —CN, —CO₂R⁷, —C(O)NR,⁷R⁷,—C(O)—R⁷, —NO₂, —OR⁷, —SR⁷, —NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷,C₁-C₁₀alkyl, C₁₋₁₀-alkenyl, C₁₋₁₀-alkoxy, C₃-C₁₀ cycloalkyl, C₆-C₁₄aryl, C₇-C₂₄ alkaryl, C₃-C₁₃ heteroaryl, C₄-C₂₃ alkheteroaryl,substituted C₁-C₁₀ alkyl, substituted C₂₋₁₀-alkenyl, substitutedC₁₋₁₀-alkoxy, substituted C₃-C₁₀ cycloalky, substituted C₄-C₂₃alkheteroaryl and Q—Ar; wherein if W is a substituted group, it issubstituted by one or more substituents independently selected from thegroup consisting of —CN, —CO₂R⁷, —C(O)R⁷, —C(O)NR⁷R⁷, —OR⁷, —SR⁷, —NR⁷R⁷, NO₂, —NR⁷C(O)R⁷, —NR⁷C(O)OR⁷ and halogen up to per-halo; wherein eachR⁷ is independently selected from H, C¹- C,₁₀ alkyl, C₂₋₁₀-alkenyl,C₃-C₁₀ cycloalkyl, C₆-C₁₄ aryl, C₃-C₁₃ hetaryl, C₇-C₂₄ alkaryl, C₄-C₂₃alkheteroaryl, up to per-halosubstituted C₁-C₁₀ alkyl, up toper-halosubstituted C₂₋₁₀-alkenyl , up to per-halosubstituted C₃-C₁₀cycloalkyl, up to per-halosubstituted C₆-C₁₄ aryl and up toper-halosubstituted C₃-C₁₃ hetaryl, wherein Q is —O—, —S—, —N(R⁷)—,—(CH₂)—_(m), —C(O)—, —CH(OH)—, —(CH₂)_(m O—, —NR) ⁷C(O)NR⁷R^(7′)—,—NR⁷C(O)—, —C(O)NR⁷—, —(CH₂)_(m) S—, —(CH2)_(m) N(R⁷)—, —O(CH₂)_(m)—,—CHX^(a), —CX^(a) ₂, —S—(CH₂)m—and —N(R⁷)(CH₂)m—, m=1-3, and X^(a) ishalogen; and Ar is a 5-10 member aromatic structure containing 0-2members of the group consisting of nitrogen, oxygen and sulfur, which isunsubstituted or substituted by halogen up to per-halo and optionallysubstituted by Z_(n1), wherein _(n1) is 0 to 3 and each Z isindependently selected from the group consisting of —CN, —CO₂R⁷,—C(O)NR⁷R⁷, —C(O)—NR⁷, —C(O)—NR⁷, COR⁷, —NO₂, —OR⁷, —SR⁷, —NR⁷R⁷,—NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C6-C₁₄ aryl,C₃-C,₁₃ hetaryl, C₇-C₂₄ alkaryl, C₄-C₂₃ alkheteroaryl, substitutedC₁-C₁₀ alkyl, substituted C₃-C₁₀ cycloalkyl, substituted C₇-C₂₄ alkaryland substituted C₄-C₂₃ alkheteroaryl; wherein the one or moresubstituents of Z is selected from the group consisting of —CN, —CO₂R⁷,—C(O)NR⁷R⁷, —OR⁷, —SR⁷, —NO₂, —NR⁷R⁷, —NR⁷C(O)R⁷, —NR⁷C(O)OR⁷ , R^(3′),R^(4′), R^(5′)are each independently H, C¹⁻¹⁰,-alkyl, optionallysubstituted by halogen, up to perhalo, C₁₋₁₀ alkoxy, optionallysubstituted by halogen, up to perhaloalkoxy, halogen; NO₂ or NH₂ ;R^(6′)is H, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, —NHCOR¹; —NR¹COR¹; NO₂;

one of R^(4′), R^(5′)or R^(6′)can be —X—Y, or 2 adjacentR^(4′)-R^(6′)can together be an aryl or hetaryl ring with 5-12 atoms,optionally substituted by C₁₋₁₀-alkyl, C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkyl,C₂₋₁₀ alkenyl, C₁₋₁₀ alkanoyl, C₆₋₁₂ aryl, C₅₋₁₂ hetaryl or C₆₋₁₂aralkyl; R¹ is C₁₋₁₀-alkyl optionally substituted by halogen, up toperhalo; X is —CH₂—, —S—, —N(CH₃)—, —NHC(O)—, —CH₂—S—, —S—CH₂—, —C(O)—,or —O—; and X is additionally a single bond where Y is pyridyl; Y isphenyl, pyridyl, naphthyl, pyridone, pyrazine, benzodioxane,benzopyridine, pyrimidine or benzothiazole, each optionally substitutedby C₁₋₁₀-alkyl, C₁₋₁₀-alkoxy, halogen, OH, —SCH₃ or NO₂ or, where Y isphenyl, by

or a pharmaceutically acceptable salt thereof.
 2. A method according toclaim 1, comprising administering a compound of formula Ia

wherein R³, R⁴, R⁵, and R⁶ are each independently H; halogen; C₁₋₁₀-alkyl optionally substituted by halogen up to perhalo; C₁₋₁₀-alkoxyoptionally substituted by at least one hydroxy group or halogen up toperhalo, C₆₋₁₂ aryl, optionally substituted by C₁₋₁₀alkoxy or halogen,C₅₋₁₂ hetaryl, optionally substitued by C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy orhalogen; NO₂; SO₂F; —SO₂CH_(p)X_(3-p); —COOR¹; —OR¹CONHR¹; —NHCOR¹;—SR¹; NH_(2;) —N(SO₂R¹)₂; fuiryloxy;

2 adjacent R³—R⁶ can together form an aryl or hetaryl ring with 5-12atoms, optionally substituted by C₁₋₁₀-alkyl, C₁₋₁₀-alkoxy,C₃₋₁₀-cycloalkyl, C₂₋₁₀-alkenyl, C₁₋₁₀—alkanoyl, C₆₋₁₂-aryl,C₅₋₁₂-hetaryl, C₆₋₁₂-aralkyl, C₆₋₁₂-alkaryl, halogen; —NR¹—NO₂; —CF₃;—COOR¹; —NHCOR¹; —CN; —CONR¹R¹; —SO₂R²; —SOR²; —SR²; in which R¹ is H orC₁₋₁₀—alkyl and R² is C₁₋₁₀-alkyl optionally substituted by halogen, upto perhalo, with —SO₂—optionally incorporated in the aryl or hetarylring; p is 0 or 1; one of R³, R⁴, R⁵ or R⁶ can be —X—Y, with the provisothat if R³ and R⁶ are both H , one of R⁴ or R⁵ is not H, andR^(3′)—R6′are as defined in claim
 1. 3. A method according to claim 2,wherein R³ is H; halogen; C₁₋₁₀-alkyl optionally substituted by halogen,up to perhalo, NO₂, —SO₂F or —SO₂CF₃; R⁴ is H, C₁₋₁₀-alkyl,C₁₋₁₀-alkoxy, halogen or NO₂; R⁵ is H, C₁₋₁₀-alkyl optionallysubstituted by halogen, up to perhalo; R⁶ is H, hydroxy, C₁₋₁₀-alkoxyoptionally substituted by at least one hydroxy group; —COOR¹;—OR¹CONHR¹; —NHCOR¹; —SR¹; phenyl optionally substituted by halo orC₁₋₁₀-alkoxy; NH_(2;) —N(SO₂R¹)₂, furyloxy, thiophene, pyrole or methylsubstituted pyrole,


4. A method according to claim 2, wherein R³ is Cl, F, C₄₋₅-branchedalkyl, —SO₂F or —SO₂CF₃; and R⁶ is hydroxy; C₁₋₁₀-alkoxy optionallysubstituted by at least one hydroxy group; —COOR¹; —OR¹CONHR¹; —NHCOR¹;—SR¹; phenyl optionally substituted by halo or C₁₋₁₀-alkoxy; NH_(2;)—N(SO₂R¹)₂, furyloxy,


5. A compound according to claim 2, wherein R^(4′)is C₁₋₁₀-alkyl orhalogen; R^(5′)is H, C₁₋₁₀-alkyl, halogen, CF₃, halogen, NO₂ or NH_(2;)and R^(6′)is H, C₁₋₁₀-alkyl, halogen, —NHCOCH₃, —N(CH₃)COCH₃, NO₂,


6. A method according to claim 2, wherein R^(5′)is C₁₋₁₀-alkyl, halogen,CF₃, halogen, NO₂ or NH₂.
 7. A method according to claim 2, whereinR^(6′)is C₁₋₁₀-alkyl, halogen, —NHCOCH₃, —N(CH₃)COCH₃, NO₂,


8. A method according to claim 4, wherein R³ is t-butyl or CF₃ and R⁶ is—OCH₃.
 9. A method according to claim 2, wherein the disease is mediatedby a cytokine or protease regulated by p38.
 10. A method according toclaim 2, wherein the disease is mediated by TNFα, MMP-1, MMP-3, IL-1,IL-6 or IL-8.
 11. A method according to claim 2, wherein the disease isan inflammatory or immunomodulatory disease.
 12. A method according toclaim 2, wherein the disease is osteoarthritis, rheumatoid arthritis,osteoporosis, asthma, septic shock, inflammatory bowel disease, or theresult of host-versus-graft reactions.
 13. A method according to claim1, wherein the compound of formula I isN-(5-tert-Butyl-2-methoxyphenyl)—N′-(4-phenyloxphenyl)urea;N-(5-tert-Butyl-2-methoxyphenyl)—N′-(4-(4-methoxyphenyloxy)phenyl)urea;N-(5-tert-Butyl-2-methoxyphenyl)—N′-(4-(4-pyridinyloxy)phenyl)urea;N-(5-tert-Butyl-2-methoxyphenyl)—N′-(4-(4-pyridinylmethyl)phenyl)urea;N-(5-tert-Butyl-2-methoxyphenyl)—N′-(4-(4-pyridinylthio)phenyl)urea;N-(5-tert-Butyl-2-methoxyphenyl)—N′-(4-(4-(4,7-methano-1H-isoindole-1,3(2H)-dionyl)methyl)phenyl)urea;N-(5-tert-Butyl-2-phenylphenyl)—N′-(2,3-dichlorophenyl)urea;N-(5-tert-Butyl-2-(3-thienyl)phenyl)—N′-(2,3 -dichlorophenyl)urea;N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)—N′-(2,3-dichlorophenyl)urea;N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)—N′-( 1-naphthyl)urea;N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)—N′-(2,3-dichlorophenyl)ureaN-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)—N′-(1-naphthyl)urea;N-(5-tert-Butyl-2-methoxyphenyl)—N′-(4-(3-pyridinyl)methylphenyl)urea;N-(5-tert-Butyl-2-(3-tetrahydrofuranyloxy)phenyl)—N′-(2,3-dichlorophenyl)urea;N-(5-Trifluoromethyl-2-methoxyphenyl)—N′-(4-methylphenyl)urea;N-(5-Trifluoromethyl-2-methoxyphenyl)—N′-(4-methyl-2-fluorophenyl)urea;N-(5-Trifluoromethyl-2-methoxyphenyl)—N′-(4-fluoro-3-chlorophenyl)urea;N-(5-Trifluoromethyl-2-methoxyphenyl)—N′-(4-methyl-3-chlorophenyl)urea;N-(5-Trifluoromethyl-2-methoxyphenyl)—N′-(4-methyl-3-fluorophenyl)urea;N-(5-Trifluoromethyl-2-methoxyphenyl)—N′-(2,4-difluorophenyl)urea;N-(5-Trifluoromethyl-2-methoxyphenyl)—N′-(4-phenyloxy-3,5-dichlorophenyl)urea;N-(5-Trifluoromethyl-2-methoxyphenyl)—N′-(4-(4-pyridinylthio)phenyu)urea;N-(5-Trifluoromethyl-2-methoxyphenyl)—N′-(4-(4-pyridinyloxy)pheny)urea;N-(5-Trifluoromethyl-2-methoxyphenyl)—N′-(3-(4-pyridinylthio)phenyl)urea;N-(5-Trifluoromethyl-2-methoxyphenyl)—N′-(4-(3-(N-methylaminocarbonyl)-phenyloxy)phenyl)-urea;N-(5-Fluorosulfonyl)-2-methoxyphenyl)—N′-(4-methylphenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(4-methylphenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(4-fluorophenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(4-methyl-2-fluorophenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(4-methyl-3-fluorophenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(4-methyl-3-chlorophenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(4-fluoro-3-chlorophenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(4-fluoro-3-methylphenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(2,3-dimethylphenyl)urea;N-(5-(Trifluoromethanesulfonyl)-2-methoxphenyl)—N′-(4-methylphenyl)urea;N-(3-methoxy-2-naphthyl)—N′-(2-fluorophenyl)urea);N-(3-Methoxy-2-naphthyl)—N′-(4-methylphenyl)urea;N-(3-Methoxy-2-naphthyl)—N′-(3-fluorophenyl)urea;N-(3-Methoxy-2-naphthyl)—N′-(4-methyl-3-fluorophenyl)urea;N-(3-Methoxy-2-naphthyl)—N′-(2,3-dimethylphenyl)urea;N-(3-Methoxy-2-naphthyl)—N′-( 1 -naphthyl)urea;N-(3-Methoxy-2-naphthyl)—N′-(4-(4-npyrdnythyl)phnlurea; N-4-Methoxy-2-naphthyl)—N′-(4-(4-pyridinylthio)phenyl)urea;N-(3-Methoxy-2-naphthyl)—N′-(4-(4-pyridinylpthylo)phenyl)urea;N-(3-Methoxy-2-naphthyl)—N′-(4(4-methoxyphenyloxy)phenyl)urea; andN-(3-Methoxy-2-naphthyl)—N′-(4-(4-(4,7-methano- 1 H-isoindole- 1,3(2H)-dionyl)methyl) phenyl)urea.N-(2-Hydroxy-4-nitro-5-chlorophenyl)—N′-(phenyl)urea; orN-(2-Hydroxy-4-nitro-5-chlorophenyl)—N′-(4-(4-pyridinylmethly)phenyl)urea.14. A compound of formula II

wherein R³, R⁴, R⁵, and R⁶ are each independently H; halogen; C₁₋₁₀-alkyl optionally substituted by halogen up to perhalo; C₁₋₁₀-alkoxyoptionally substituted by at least one hydroxy group; NO₂; SO₂F;—SO₂CH_(n)X_(3-n)—COOR¹; —OR¹CONHR¹; —NHCOR¹; —SR¹; C₆₋₁₂ aryl,optionally substituted by C₁₋₁₀-alkyl, C₁₋₁₀ alkoxy or halogen, C₅₋₁₂hetaryl, optionally substitued by C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy or halogen;NH₂; —N(SO₂R¹)₂; furyloxy;

2 adjacent R³-R⁶ can together form an aryl or hetaryl ring with 5-12atoms, optionally substituted by C₁₋₁₀-alkyl, C₁₋₁₀-alkoxy,C₃₋₁₀-cycloalkyl, C₂₋₁₀-alkenyl, C₁₋₁₀-alkanoyl, C₆₋₁₂-aryl ,C₅₋₁₂-hetaryl, C₆₋₁₂-aralkyl, C₆₋₁₂-alkaryl, halogen; NR¹R¹, NO₂; —CF₃;—COOR¹; —NHCOR¹; —CN; —CONR¹R¹; —SO₂R²; —SOR²; —SR²; in which R¹ is H orC₁₋₁₀-alkyl and R² is C₁₋₁₀-alkyl; C₁₋₁₀-alkoxy, optionally substitutedby halogen up to perhaloalkoxy, R^(3′), R4′and R^(5′)are eachindependently H, C₁₋₁₀-alkyl, optionally substituted by halogen, up toperhalo; halogen; NO₂ or NH₂; R^(6′)is H, C₁₋₁₀-alkyl, halogen, —NHCOR¹;—NR¹COR¹; NO₂;

or 2 adjacent R^(4′)-R^(6′)can together be an aryl or hetaryl ring with5-12 atoms; R¹ is C₁₋₁₀-alkyl; n is 0 or 1; X is —CH₂—, —S—, N(CH₃)—,—NHC(O), CH₂—S—, —S—CH₂—, —C(O)—, or —O—; and Y is phenyl, pyridyl,naphthyl, pyridone, pyrazine, benzodixane, benzopyridine, pyrimidine orbenzothiazole, each optionally substituted by C₁₋₁₀-alkyl, C₁₋₁₀-alkoxy,halogen or NO₂ or, where Y is phenyl, by

or a pharmaceutically acceptable salt thereof, with the provisos that(a) if R³ and R⁶ are both H, one of R⁴ or R⁵ is not H, (c) R⁶ is phenylsubstituted by halogen, alkoxy substituted by hydroxy, —SO₂CF₂H,—OR¹CONH¹,

(c) the compounds have a pKa greater than
 10. 15. A compound accordingto claim 14, wherein R³ is H, halogen or C₁₋₁₀-alkyl optionallysubstituted by halogen, up to perhalo, NO₂, —SO₂F or —SO₂CF₃; R⁴ is H,C₁₋₁₀-alkyl, C₁₋₁₀-alkoxy, halogen or NO₂; R⁵ is H, C₁₋₁₀-alkyloptionally substituted by halogen, up to perhalo; R⁶ is H, hydroxy,C₁₋₁₀-alkoxy optionally substituted by at least one hydroxy group;—COOR¹; —OR¹CONHR¹; —NHCOR¹; —SR¹; phenyl optionally substituted by haloor C₁₋₁₀-alkoxy; NH_(2;) —N(SO₂R¹)₂, furyloxy,


16. A compound according to claim 14, wherein R³ is Cl, F. C₄₋₅-branchedalkyl, —SO₂F or —SO₂CF₃; and R⁶ is hydroxy; C₁₋₁₀-alkoxy optionallysubstituted by at least one hydroxy group; —COOR¹; —OR¹CONHR²; —NHCOR¹;—SR¹; phenyl optionally substituted by halo or C₁₋₁₀-alkoxy; NH_(2;)—N(SO₂R¹)₂, furyloxy,


17. A compound according to claim 14, wherein R^(4′)is C₁₋₁₀-alkyl orhalogen; R^(5′)is H, C₁₋₁₀-alkyl, halogen, CF₃, halogen, NO₂or NH₂; andR^(6′)is H, C₁₋₁₀-alkyl, halogen, —NHCOCH₃, —N(CH₃)COCH₃, NO₂,


18. A compound according to claim 14, wherein R³ is t-butyl or CF₃ andR⁶ is —OCH₃.
 19. A compound according to claim 14, which isN-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)—N′-(2,3-dichlorophenyl)urea;N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)—N′-(1-naphthyl)urea;N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)—N′-(2,3-dichlorophenyl)urea;N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)—N′-(1-naphthyl)urea;N-(5-tert-Butyl-2-(3-tetrahydrofuranyloxy)phenyl)—N′-(2,3-dichlorophenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(4-methylphenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(4-fluorophenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(4-methyl-2-fluorophenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(4-methyl-3-fluorophenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(4-methyl-3-chlorophenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(4-fluoro-3-chlorophenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(4-fluoro-3-methylphenyl)urea;N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)—N′-(2,3-dimethylphenyl)urea;orN-(5-(Trifluoromethanesulfonyl)-2-methoxphenyl)—N′-(4-methylphenyl)urea.20. A compound of formula II

wherein R³R⁴, R⁵, and R⁶ are each independently H; halogen; C₁₋₁₀- alkyloptionally substituted by halogen up to perhalo; C₁₋₁₀-alkoxy optionallysubstituted by at least one hydroxy group; NO₂; SO₂F;—SO₂CH_(n)X_(3-n),; —COOR¹; —OR¹CONHR¹; —NHCOR¹; —SR¹; phenyl optionallysubstituted by halogen or C₁₋₁₀-alkoxy; NH_(2;) —N(SO₂R¹)₂; fuiryloxy;

2 adjacent R³-R⁶ can together form an aryl or hetaryl ring with 5-12atoms, optionally substituted by C₁₋₁₀-alkyl, C₁₋₁₀-alkoxy,C₃₋₁₀-cycloalkyl, C₂₋₁₀-alkenyl, C,₁₋₁₀-alkanoyl, C₆₋₁₂-aryl,C₅₋₁₂-hetaryl, C₆₋₁₂-aralkyl, C6-12-alkaryl, halogen;—NR¹; —NO₂; —CF₃;—COOR¹; —NHCOR¹; —CN; —CONR¹R¹; SO₂R²; SOR²; —SR²; in which R¹ is H orC₁₋₁₀-alkyl and R² is C₁₋₁₀-alkyl; R3′, R^(4′)and R^(5′)are eachindependently H, C₁₋₁₀-alkyl, optionally substituted by halogen, up toperhalo; halogen; NO₂ or NH₂;

R^(6′) is H, C₁₋₁₀-alkyl, halogen, —NHCOR¹; —NR¹COR¹; NO₂; R¹isC₁₋₁₀-alkyl; n is 0 or 1; X is —CH₂—, —S—or —O—; and Y is phenyl,pyridyl, naphthyl or benzothiazole, each optionally substituted byC₁₋₁₀-alkyl, C₁₋₁₀-alkoxy, halogen or NO₂ or, where Y is phenyl, by

or a pharmaceutically acceptable salt thereof with the provisos that (a)if R³ and R⁶ are both H, one of R⁴ or R⁵ is not H, and (b) R⁶ is alkoxysubstituted by hydroxy, —SO₂CF₂H, —OR¹CONHR¹,


21. A pharmaceutical composition comprising a compound of claim 14, anda physiologically acceptable carrier.
 22. A pharmaceutical compositioncomprising a compound of claim 20, and a physiologically acceptablecarrier.